Dr. John Cleveland
When John Cleveland accepted the chairmanship of Scripps Florida's new Department of Cancer Biology in the fall of 2006, he had his sights set high.
"The idea is to conduct outstanding discovery-based basic research in cancer biology and then to apply it using the high-throughput facilities available at Scripps Florida," he said. The goal, he continued, "is to try to make real drugs by collaborating with the medicinal chemistry program at Scripps Florida and with cancer centers in the State of Florida to move these drugs into Phase I trials."
Now, with a recent major breakthrough for pediatric patients, Cleveland and his team are well on the path to realizing the ambitious goals they laid out for themselves - and making a real difference in the lives of hundreds of thousands of patients.
Cleveland's work on MYC (a transcription factor whose over-expression is associated with cancer) led him to investigate a compound called a-difluoromethylornithine or DFMO. DFMO targets the activity of a specific enzyme, and Cleveland's team found that, even in limited doses, it is effective in protecting against malignancy.
"The drug, which was developed as a cancer therapy and later shelved because of toxicity concerns, has been around since the 1970s," said Cleveland. "But over the past five years, it has undergone a rebirth as a chemoprevention agent, first showing efficacy in animal models of human cancer and more recently in human prostate and colon cancer. Our study shows that it likely works in a large cast of tumors, even those having poor prognosis, like high-risk neuroblastoma."
Neuroblastoma is a childhood malignancy of the sympathetic nervous system (part of the nervous system that serves to accelerate the heart rate, constrict blood vessels, and raise blood pressure) that accounts for nearly eight percent of all childhood cancers and 15 percent of pediatric cancer-related deaths. Neuroblastoma usually occurs in infants and young children, appearing twice as frequently during the first year of life than in the second.
Aiming to stop neuroblastoma in its tracks, Cleveland's team first focused on MYCN, a proto-gene whose overexpression is associated with neuroblastoma, particularly the high-risk form of the disease. MYCN proves a difficult therapeutic target since it also produces proteins that are required for the growth of most normal cell types.
Instead, Cleveland's team shifted its focus to ornithine decarboxylase (Odc), a protein that contributes to cancer cell growth and that is a target of MYCN. Increased levels of Odc are common in cancer, and forced Odc expression has been shown to lead to increased tumor incidence. Furthermore, recent findings have shown that Odc overexpression is also an indication of poor prognosis in neuroblastoma.
Knowing that the formerly shelved DFMO inhibits the activity of Odc, Cleveland's team set about testing its effect on preventing neuroblastoma.
"We were able to prevent neuroblastoma caused by MYCN, delaying the onset and incidence of this tumor type," said Cleveland. "What's even more compelling, we used low doses of the drug, and DFMO only had to be given for a moderate amount of time to prevent cancer."
While there are valid safety concerns to be addressed regarding DFMO, Cleveland's study provides the vital knowledge that the Odc pathway may offer novel therapeutic angles for fighting neuroblastoma and a wide range of cancers.
When other researchers had turned their attention elsewhere, seeing that a drug would not be immediately viable, Scripps Research enabled Cleveland's team to investigate the biomedical foundation of the shelved drug and provide new knowledge about potential drug pathways. It was this sort of scientific independence that drew Cleveland to Scripps Research, and it is the foundation upon which his Department of Cancer Biology is built.
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