Mr. Protein Head? For most of its serious chaperoning, HSP90 functions as part of so-called super-chaperone complexes of HSPs. In fact, HSP90 actually directs their formation. "It's like a Mr. Potato Head," Dr. Neckers says. "It serves as an assembling point for other chaperone proteins." These HSP complexes lie at the center of 1 theory behind the fact that 17-AAG has at least 20 times more affinity for HSP90 in cancer cells than it does in normal cells. Nobody has proven why this occurs, but the theory holds that in a normal cell, HSP90 is relatively dormant because there is little stress for it to react to. But as Dr. Whitesell explains, "Cancer cells, unlike normal cells, are already at their margin in utilizing their full HSP90 capacity…so it's highly activated and more sensitive to the drug."

The cancer cell differs from a normal cell in several ways. One big difference is that a cancer cell can survive, and in some cases thrive, under environmental assaults - such as the severe lack of oxygen in tumors or even the onslaught of cytotoxic chemotherapy agents - that would destroy a normal cell.

These remarkable survival skills are due in no small part to a family of proteins spurred to action by stress in the cellular environment. These so-called heat shock proteins (HSPs) serve as both molecular mechanics and bodyguards to other proteins. Stressed intracellular proteins that begin to misfold, for instance, are quickly repaired. Mutated proteins that otherwise would be shuttled away by the cell for degradation are somehow aided in carrying out their tasks as transcription factors, hormone receptors, and the like.

One HSP in particular, HSP90, has fascinated researchers because many of its "client" proteins - those that require HSP90's chaperoning skills in both normal and stress-laden environments - also are members of the most-wanted list of proteins that spur cancer development and growth, including mutant p53, Bcr-Abl, HER-2, HIF-1, and many others.

Therein lies HSP90's potentially immense therapeutic value, says Dr. Len Neckers, a senior principal investigator in NCI's Urologic Oncology Branch, who has been a leader in HSP90 research.

"By inhibiting HSP90, you avoid focusing on a specific step in cancer development, which, as we're beginning to see, tends to allow cancers to evade molecularly targeted attacks," he says. "By inhibiting HSP90, we're simultaneously attacking multiple signaling nodes of a cancer cell's survival network."

In 1993, Dr. Neckers and his NCI colleagues discovered that a common, off-patent antibiotic, geldanamycin, could inhibit HSP90's chaperoning function. It was the first such discovery, and it launched an onslaught of research at institutions across the country and the world to delve deeper into HSPs in terms of their functionality and anticancer potential.

Jump ahead more than a decade, and five phase I trials testing a geldanamycin derivative, 17-AAG, developed at NCI in collaboration with the pharmaceutical company Kosan Biosciences, have now been completed in the United States and the United Kingdom. None, Dr. Neckers says, was a "home run," but that's typical for phase I trials, which are principally intended to establish safety measures, such as the maximum dose at which clinical and/or biological activity can be detected without causing life-threatening toxicities.

However, in a phase I trial of 17-AAG conducted in the United Kingdom on patients with a variety of solid tumors, two patients with advanced melanoma had sustained periods of stable disease, one of which lasted for nearly 4 years, says the study's leader, Dr. Ian Judson of the Institute of Cancer Research.

More than 20 phase II trials of 17-AAG - alone, or in combination with chemotherapy or targeted agents - are under way. The trials cover a broad range of indications, including advanced breast cancer, prostate cancer, and an assortment of leukemias.

Dr. Jeff Moley from the Siteman Cancer Center of the Washington University School of Medicine is leading a phase II trial of 17-AAG to treat two different kinds of thyroid cancer, including medullary thyroid cancer (MTC). RET, the protein that fuels MTC, is yet another HSP90 client, and Dr. Moley's research has demonstrated that 17-AAG inhibits RET activity.

"There is no standard of care for MTC patients with distant metastases who are no longer taking up radioactive iodine," Dr. Moley says. With 17-AAG, he adds, "We are plowing new ground."

The drug is also being tested in patients with chronic myelogenous leukemia who have developed resistance to perhaps the most famous and effective targeted drug, imatinib (Gleevec).

As it turns out, says Dr. Luke Whitesell, a pediatric oncologist at the University of Arizona currently on leave at the Whitehead Institute for Biomedical Research in Massachusetts, imatinib-resistant leukemia cells "retain their sensitivity for geldanamycin and, if anything, become more sensitive to it."

Dr. Whitesell, who was part of Dr. Neckers' team that discovered geldanamycin's prowess for inhibiting HSP90, is focusing much of his research on HSP90's role in allowing cancer cells to evolve and develop resistance to a given treatment.

"Acquired resistance is a fundamental barrier to curing many cancers," he says. "Within tumors, you've got a genetically unstable and heterogeneous population of cells with tremendous selective pressures placed on them. Evolution to more malignant, drug-resistant phenotypes over time is an inevitable, but poorly understood consequence."

His theory is that HSP90 not only moderates the impact of potentially lethal mutations in cancer cells, but also can preserve those mutations that confer resistance.

"If you could control cancer cells' ability to evolve, it could make other treatments more effective," he argues. In fact, cell line and animal model studies of cervical and lung cancer have shown that 17-AAG can enhance the effectiveness of what would otherwise be suboptimal radiation therapy.

Work is already under way at NCI and several small biotechnology companies to develop next-generation HSP90 inhibitors. 17-DMAG, an agent developed at NCI in collaboration with Kosan, is now in phase I trials. At least six other companies/laboratories are working on their own novel HSP90 inhibitors.

By Carmen Phillips