© 2002 by Oxford University Press
Journal of the National Cancer Institute, Vol. 94, No. 16, 1194-1195,
August 21, 2002
© 2002 Oxford University Press
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Heat Shock Protein Inhibitor Shows Antitumor Activity
In an oncologic twist of the classic happenstance discovery of penicillin, fungus-derived antibiotics are moving toward phase II clinical trials for their anti-tumor effects in hard-to-treat leukemia, breast, prostate, lung, and ovarian cancers.
Several rounds of laboratory, animal, and early human studies have produced encouraging results with the drug 17-allylaminogeldanamycin (17AAG), used as a single agent or in combination with conventional chemotherapy. The drug appears to work by interfering with heat shock protein 90 (Hsp90), a stress-induced molecule abundant in tumor cells.
The National Cancer Institute is manufacturing 17AAG for current and future clinical studies. Pharmaceutical companies usually fill this role, but they have been slow to pick up on 17AAG and sibling drugs, because little intellectual property protection exists for molecules found in nature. Patents held by a Japanese firm further reduce profit potential.
Nonetheless, phase I safety studies at the National Institutes of Health, the University of Pittsburgh, Memorial Sloan-Kettering Cancer Center, the Mayo Clinic, and the Cancer Research Council of England are nearing completion, with published results expected within 6 months. These studies have pinned down once-weekly intravenous injections as the most effective, least toxic treatment schedule, said Leonard Neckers, Ph.D., chief of the tumor cell biology section at NCI.
Neckers has been studying fungal antibiotics since the early 1990s, although his interest in these drugs was as accidental as Alexander Fleming’s. In 1992, reports surfaced that the class of antibiotics known as benzoquinone ansamycins could inhibit tumor cells. It was thought that the antibiotics interfered with tyrosine kinases, well-studied as intracellular communication links that go awry during tumor formation.
Picking up on the kinase theme for an unrelated study, Neckers and his colleagues soon discounted a direct effect on kinase activity as the source of anti-tumor effects. Curiosity piqued, they ran a series of experiments that yielded huge amounts of a protein with a mass of 90 kilodaltons that appeared to be involved with 17AAG activity. "We thought, well, what molecule weighing that much is abundant in tumor cells?" recalled Neckers. Maybe it was Hsp90.
At the time, little was known about the protein. But antibody assays for the recently described molecule did exist. Neckers’ laboratory obtained the necessary reagents and ran more experiments. Sure enough, the product they had isolated earlier was Hsp90, a finding they published in Proceedings of the National Academy of Sciences in 1994.
The serendipitous laboratory encounter changed the course of Neckers’ career dramatically. "I knew nothing about heat shock proteins to begin with," he said. Instead, he was devoted to antisense molecules, which in the early 1990s had been hyped as the next big cancer treatment. Neckers even held stake in a few antisense molecule patents that the NCI had licensed to biotechnology companies. But as intrigue built with each Hsp90 experiment, Neckers abandoned his work with antisense molecules. His laboratory is now "100 percent Hsp90."
The discovery that fungal antibiotics block Hsp90 garnered excitement in the tiny, growing milieu of heat shock protein research; the finding offered a means to ferret out Hsp90’s cellular role. In tumor cells, that role turned out to be huge. "If you make a list of mutated molecules that can cause cancer, many are clients of Hsp90," said Neckers.
Formed in response to stress (and first seen in overheated cells) heat shock proteins protect other proteins—the clients—during their construction. Known as "cellular chaperones," heat shock proteins wrap around newborn molecules. Safe and snug, the proteins survive and go about their life-sustaining business.
But the molecules can mutate. These malevolent proteins—deformed p53, bcr-abl, HER2, and others—incite cellular immortality and tumor formation. Hsp90 keeps the proteins safe as they wreak their havoc.
Its action on a wide range of mutant proteins makes Hsp90 especially attractive as a drug target: A proper inhibitor could cripple each of the proteins and treat a broad range of tumors. In bench and animal studies, 17AAG does just that, ultimately killing tumor cells outright or at least slowing their growth. The drug also appears to reverse resistance to doxorubicin and other chemotherapy agents.
As the phase I safety studies of 17AAG wrap up, several phase II trials are in the works. Its action against bcr-abl makes it an ideal candidate for chronic myelogenous leukemia patients whose tumors do not respond to Gleevec (STI-571). Its action against HER2 makes it ideal for treating 30% to 40% of breast, ovarian, and non-small-cell lung cancers. Its action against the androgen receptor makes it ideal for treating some prostate cancers. As more Hsp90 research is published, this impressive list could grow.
But to realize this promise, a pharmaceutical company will eventually have to invest. The NCI set a natural-products precedent with paclitaxel, an unpatentable compound isolated from pine trees, by developing and then licensing the manufacturing process to Bristol-Myers Squibb. Although NCI has weathered severe criticism for selling a billion-dollar blockbuster for relative pennies, the institute has followed suit with an umbrella patent on the 17AAG formulation process.
As yet, though, no corporate customers have expressed interest. The quickest route to market may instead be the development of a synthetic derivative. Neckers said that several laboratories are tinkering with the molecular structure of 17AAG, working toward a safe, effective, and—most importantly, it appears—patentable and profitable compound.
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