NEWS

Designer Molecule May Lead to New Treatments for Ocular Cancers

James Schultz

Cure rates for nonmetastasized ocular cancer are very high—but at a steep price. Despite advances in radiation, chemotherapy, and laser therapies, enucleation, or surgical removal of the eye, is associated with the highest rate of cure. For adults, enucleation is tragedy enough. For children born with a genetic predisposition to eye cancer, enucleation can prove an even crueler fate, stealing vision just several years after birth and before language is even acquired or mastered.

As an alternative to eye removal, and to reduce intraocular tumor size or destroy tumors outright, physicians are exploring innovative uses of ultrasound, heat, cryogenics, targeted radiation "seeds," even reengineered viruses. The ultimate goal is to preserve the eye, at least for as long as is medically feasible, and perhaps long enough for alternative effective approaches to be developed.

"It can be complicated for an opthamologist," said Curtis R. Brandt, Ph.D., vice chair for research in the Department of Opthamology and Visual Sciences at the University of Wisconsin Medical School in Madison, and professor of opthamology and visual sciences and medical microbiology and immunology. "You can get a wide variety of cancer growth rates. Obviously you’d rather not take someone’s eye out. But you’re weighing the possibility [that the cancer] will go metastatic. You certainly don’t want it to spread."

The American Cancer Society estimates that roughly 2,200 new cases of primary intraocular cancers present annually, with most occurring in people older than age 50. Compared with other cancers, overall death rates are low, on the order of 200 each year.

Research Funding

Brandt noted that ocular cancer’s relative rarity means that research dollars are hard to come by because higher-prevalence cancers receive first consideration. "For a long time, ocular cancer has been an orphan cancer," he asserted. "It can be difficult to convince [the funders] to underwrite the research. So we really don’t know a lot about it. We don’t have good markers."

One unique therapeutic approach under development may push ocular cancers to the treatment forefront. J. William Harbour, M.D., associate professor in the Division of Molecular Oncology at the Washington University School of Medicine, St. Louis, Mo., is directing an effort to restore normal cellular function in eye tumors. The goal is to essentially reclaim cancer-hijacked mechanisms that trigger apoptosis, or programmed cell death, thereby short-circuiting tumor growth at its source.

Novel Molecule

Harbour and his Washington University research group have devised a novel molecule they have christened Tat-anti-HDM2. The name is derived from both the reengineered virus used to deliver the molecule and a key protein that prevents cell death from taking place. In normal cells, the suppressor factor known as p53 usually prevents tumor development. But cancers are able to overexpress a p53 inhibitor protein known as HDM2, which ensures tumor survival by preventing apoptosis. Harbour’s "competitive inhibition" strategy is to prevent HDM2 from interfering with p53 by flooding its p53 binding site with his group’s designer molecule. That way, p53 can go about its business unimpeded.

Harbour and his colleagues attached the p53 peptide to a peptide derived from the "Tat" protein, which is expressed by HIV, the human immunodeficiency virus. Tat’s structure allows it easy and rapid passage across cell membranes. The group initially tested Tat in cultured cells—cancerous and noncancerous—and then proceeded to inject Tat-anti-HDM2 into human retinoblastoma cells that had been placed into the eye of a rabbit and allowed to mature into several formed tumors. The results—both in culture and the animal model—were striking.

Within four hours, p53 levels increased a thousand-fold in the in vitro tests. Within 8 hours, apoptosis began. Within 24 hours, more than 80% of the cancer cells began to die. Normal cells were unaffected. In the animal model, 95% of the rabbit eye tumors treated with the Tat-anti-HDM2 molecule were destroyed. A control peptide administered to other tumors had minimal effect. And there was no damage to otherwise healthy ocular tissue.

"Because we grew the tumors in the front part of the eye, you could actually see them dissolving," Harbour said. "You could see and understand what was happening. All cancer cells have defects in apoptosis. That’s why I think p53 is the way to go."

Harbour said he believes this approach could boost the effectiveness of conventional therapies, particularly radiation and chemotherapy, in the treatment of the two most common eye cancers, uveal melanomas and retinoblastomas. A designer molecule, for instance, could allow physicians to radiosensitize eye tumors, permitting a much lower but much more effective dosage, perhaps reducing the risk of later-onset eye cancers.

Stopping Further Growth

Currently, even successful radiation treatments will not prevent additional ocular cancer from developing. The younger the patient, the higher the risk. For a child whose eye tumors are successfully treated with radiation, for example, there is a 50% chance that more tumors will grow by age 30, reported Richard L. Hurwitz, M.D., associate professor of pediatrics, cell biology and opthamology at the Baylor College of Medicine in Houston.

Harbour’s studies are still in a preliminary, preclinical phase and additional work must be done to refine the molecules for use in humans. Because such molecules make use of a common cellular pathway, they hold the potential to overcome multidrug resistance, a common problem with conventional chemotherapy. In principle, designer molecules that prevent or kill cancers by restoring healthy cell behaviors could have application in other cancers, such as those of the lung, breast, skin, and prostate.

"I have a lot of respect for Bill’s work," Hurwitz said. "We have a lot of interest in the way he’s designing his peptides. That concept has a lot to offer. That approach could work not just in ocular cancers but in other cancers as well."

Hurwitz and his colleagues at Baylor are exploring means of increasing tumor vulnerability to antibiotics by inserting a modified herpes viral gene that bears the increased susceptibility directly into ocular cancer cells. Antibiotics can then be administered, killing the tumors. Hurwitz is in the middle of phase I trials, with seven patients treated to date. Despite promising early results in his trial and in the animal models overseen by Harbour, there appears to be no one easy solution to ocular cancer treatment.

"Cancer is a complex disease with multiple mutations that accumulate over time," Harbour pointed out. "Realistically, I envision a combination of agents given sequentially that would target and disrupt different cancer mechanisms. History would tell us there is no one magic bullet."



             
Copyright © 2002 Oxford University Press (unless otherwise stated)
Oxford University Press Privacy Policy and Legal Statement