RB, uveal melanoma research opens door for understanding other cancers

Uveal melanoma . . . and most solid tumors partially inactivate RB and the tumors proliferate slowly with a low rate of apoptosis.

"These eye cancers, despite their rarity, have an influence well beyond their prevalence. We started with clinical observations that led to basic science discoveries, biological insights, and exponential cross-fertilization with other fields that have already led to clinical impact," he said. "In the future we expect more clinical impact. The research that we conduct extends far beyond ocular oncology to all areas of oncology."

Dr. Harbour, associate professor, and director of the ocular oncology service at Washington University School of Medicine, St. Louis, is the winner of the 2005 Cogan Award for his significant contributions to the understanding of the molecular regulation of the cell cycle in ocular tumors. The Cogan Award recognizes a researcher, 40 years or younger at the time of nomination, who has made important contributions to research in ophthalmology and visual science directly related to disorders of the human eye or the visual system.

Dr. Harbour described recent discoveries in oncology research including the activity of the RB gene mutation, which is present in many other cancers. Retinoblastoma, while rare, is the most common ocular cancer in children. In the United States, 95% of children with RB survive, but worldwide, most die.

"Scientifically, the genetics of RB have provided a clue to the revolution in cancer research 20 years ago," Dr. Harbour explained. "The basic observation was that there were two forms of retinoblastoma. One form develops in only one eye and is not passed on to children, and the other form develops in both eyes and it is passed on to children."

This discovery accounted for the different inheritance pattern based on the presence of a recessive cancer gene, which was a revolutionary idea at the time. It resulted in the understanding that the RB gene mutation had different patterns; either it was partly or completely missing or there were gross rearrangements. A parallel discovery was that the RB gene mutation also appears in small-cell lung cancer, other lung cancer, and breast cancer.

RB protein

The real revolution started, he pointed out, when investigators began looking at the RB protein. Virtually every cancer studied has some defect that inactivates the RB protein. The important factors associated with the RB protein are that there are 16 sites where it can be phosphorylated and the "business end" of the molecule has a pocket with two boxes that allows multiple proteins to bind to it.

"Binding at the molecular level represses gene expression," according to Dr. Harbour.

Further research showed that the RB protein is regulated differently. Uveal melanoma, the most common primary ocular cancer in adults, and most solid tumors partially inactivate RB and the tumors proliferate slowly with a low rate of apoptosis. Conversely, retinoblastomas, small-cell lung cancer, and high-grade melanomas delete RB and there is rapid proliferation of the tumor with a high rate of apoptosis.

"There are at least two tumor suppressor mechanisms by which RB blocks tumor formation," he said. "The primary one is regulation of the cell cycle. The apoptotic response, we think, is the 'last-ditch' tumor suppressor mechanism when a tumor cell escapes the primary mechanism before becoming cancerous."

Tumors that partially inactivate RB do so by inactivating p16, a tumor suppressor gene, or by overexpressing cyclin D. This usually leads to slow proliferation, and the advantage for the tumor cell is that the apoptotic response is not triggered.

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