MICHAEL GREVER ON SECOND CHANCES
BY C H U C K S TA R E S I N I C
ichael Grever (MD ’71, Res ’74) has learned that believing in second chances can pay off. An experimen- tal drug he championed that once seemed ineffective now shows promise for leukemia patients. M
Grever, who also received his undergradu- ate chemistry degree from Pitt and was rec- ognized recently as one of the University’s Legacy Laureates, was a full professor in the Department of Internal Medicine at Ohio State University in the 1980s. There, he ran some of the first clinical trials of new can- cer drugs. He would receive drugs from the National Institutes of Health (NIH) with instructions. His job was to determine their efficacy and to evaluate, when something went wrong, whether it was because of the new therapy or the underlying disease. Later, at the National Cancer Institute (NCI), he learned how the instructions were written. In 1989, Grever became deputy director of the NCI’s Division of Cancer Treatment and Diagnosis.
Grever eventually directed the institute’s drug discovery and drug development pro- grams for cancer and AIDS. His team cracked open the molecular biology of exotic new compounds in search of targeted cancer thera- pies. They brought the most promising ones forward through animal studies until they were ready for clinical trials.
“As a result, we put about 19 to 21 new
An experimental leukemia drug Grever champion
therapies into patients with cancer or AIDS,” he says, including pentostatin and fludarabine.
In the early 1990s, Grever and colleagues at the NCI began looking at a drug called flavo- piridol as a treatment for chronic lymphocytic leukemia (CLL). In the Petri dish, it was a win- ner. There was a lot of excitement about mov- ing it into Phase I testing in humans. When they tried it in patients, however, it bombed.
“It didn’t do anything,” says Grever. “It just produced diarrhea, and that wasn’t a very attractive side effect.” These disappointing results were repeated across the United States and in Europe. Before long, the drug company decided to drop the project, and the NIH began to lose interest, too. But Grever wanted an explanation.
In the lab, his team took human leukemia cells suspended in the patient’s own plasma and figured out how much drug was needed to kill the cancer cells. It took a much higher con-
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ed actually kills cancer too fast.
centration of drug than anyone had thought it would. Why? The original lab tests used fetal calf serum, because human plasma is prohibi- tively expensive. Most of the drug was bound to human plasma protein and unavailable for killing cancer—something that hardly hap- pened at all in calf serum.
Grever personally lobbied the NIH and the drug company to test flavopiridol again with different dosages and a new schedule of drug administration. These studies were conducted in his research laboratory at Johns Hopkins University. Shortly therafter, he was back at Ohio State as chair of internal medicine—a position where he could make the drug a prior- ity. In clinical trials, Grever says, the drug “was so effective that, for a while, it was killing the leukemic cells too fast. We went to the FDA, and they said, ‘Well, you can’t give up on this, because it’s very promising.’”
In fact, the rapid destruction of a large number of cancer cells can cause a major problem, because the body must clean up the mess and the toxic byproducts. Grever hopes flavopiridol can be used in combination with other proven leukemia drugs to achieve com- plete remission. He and colleagues reported the latest news on flavopiridol this January in the journal Blood, but there will soon be more. They have a Phase II study in CLL patients under wa , and other institutions are trying to reproduce their work.
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“We’ve treated over 80 patients,” Grever says, “and this is all holding up. This is going to be one of the most active agents in the treat-
ment of this disease.