BioWorld International Correspondent

LONDON - The first clinical trial of an entirely new class of cancer drugs has delivered exciting results, including the first indication that it might be able to halt the disease in patients.

The Phase I trial assessed the safety and toxicity of a drug called 17AAG, which inhibits heat-shock protein 90, or HSP90, and found molecular evidence that the drug can inhibit its target in patients' tumors.

Two people with malignant melanoma who took part in the trial entered stable disease, where their tumors failed to progress. Those individuals lived for 15 months and five years while taking 17AAG, although the average life expectancy for people with late-stage malignant melanoma for whom other treatments have failed is six to 12 months.

Researchers now are embarking on two Phase II trials. One of those is being conducted at the Royal Marsden Hospital in Sutton, Surrey, and the Royal Free Hospital in London, and the other will take place in the U.S. Those trials will evaluate the efficacy of 17AAG in treating malignant melanoma. Each will recruit about 30 patients. Further trials in the UK and the U.S. are planned, using 17AAG against other types of cancers, such as breast, prostate and kidney.

Paul Workman, director of the Cancer Research UK Centre for Cancer Therapeutics at the Institute of Cancer Research in Sutton, Surrey, told BioWorld International: "The results from this Phase I trial of 17AAG are important because this is the first clinical study of an HSP90 inhibitor, and we have shown that it does not lead to serious toxicity. The results are still early, but they are very promising. There is an interesting sign of clinical activity from the two patients who had stable disease, although we do not want to overstate the importance of this."

Workman and his colleagues reported the results in the June 16, 2005, issue of Journal of Clinical Oncology. The paper is titled "Phase I Pharmacokinetic and Pharmacodynamic Study of 17-Allylamino, 17-Demethoxygeldanamycin in Patients With Advanced Malignancies."

The research was carried out by investigators at the Institute of Cancer Research and The Royal Marsden Hospital. The drug was provided by the National Cancer Institute in the U.S. under a Cooperative Research and Development Agreement with Kosan Biosciences Inc., of Hayward, Calif.

When cells are subjected to heat stress, they make more of certain proteins, collectively called the heat-shock proteins. Many, of which HSP90 is one, have turned out to be "molecular chaperones" - proteins that help to fold and stabilize other proteins in the cell.

Some studies suggested that inhibiting HSP90 could induce cancer cells to enter apoptosis, or at least arrest the growth of cancer cells. Further investigations showed that, fortuitously, HSP90 is not an all-purpose molecular chaperone, but one that deals with only about 10 percent of proteins - many of them involved in cancer.

The proteins on HSP90's "client list" include, for example, Raf, ErbB2, BCR-ABL and mutant p53. Workman explained: "If you inhibit HSP90, you block the correct folding and regulation of a whole list of proteins known to be needed by cancer cells, including those required to block apoptosis, for proliferation, for metastasis and for invasion." In addition, when HSP90 is inhibited, its client proteins are marked for disposal by the proteosome - the "cellular dustbin."

All those factors together, he added, mean that inhibiting HSP90 causes a blockade of multiple pathways needed by cancer cells. "We anticipate that, as a result, 17AAG has a very powerful, combinatorial effect on cancer cells, and that this will reduce the chance of resistance occurring. These great aspects of the drug explain why we are so excited about it," Workman said.

The Phase I trial reported in the Journal of Clinical Oncology aimed to establish an appropriate and tolerable dose for 17AAG in 30 patients with advanced cancer. Experiments carried out for the study showed that it was possible to achieve a biologically active dose, and at that dose, the drug could inhibit the HSP90 target in the tumor.

Workman predicted that the findings will spur on companies and other academic groups to develop more drugs that inhibit HSP90.

No Comments