HIV Drugs Show Promise Fighting Cancer in Preclinical Studies
NCI investigators have shown that nelfinavir (Viracept) and two other protease inhibitors, drugs developed and approved to fight HIV infection, may have a role in treating cancer. The research illustrates the promising strategy of broadening the use of these inhibitors that have already shown efficacy against HIV/AIDS to include cancer treatment.
Results published in the September 1 Clinical Cancer Research showed that three of six drugs used to treat HIV/AIDS also inhibit an important target in cancer, Akt, stopping the growth of cancer cells, not only in vitro, but also when those cells are transplanted into mice.
These results have encouraged Dr. Phillip Dennis, whose laboratory in the Medical Oncology Branch of NCI's Center for Cancer Research (CCR) conducted the study, to begin a phase I trial, testing nelfinavir in people with a wide range of solid tumors that have progressed after treatment with standard therapies.
"Based on the in vitro work, we're hopeful that giving patients larger doses of nelfinavir than are used to treat HIV will be effective against their cancers," said Dr. Dennis. In phase I trials, researchers are determining how much of the drug can be safely given - the maximum tolerated dose - and how the drug actually works in the body.
At the same time, a phase I/II study testing nelfinavir in patients with liposarcoma is also underway.
To determine whether a group of protease inhibitors presently FDA-approved for treating HIV/AIDS also might be applicable to cancer, Dr. Dennis' team performed a number of experiments with cell cultures and tumor-bearing mice. First, the researchers found that nelfinavir was most potent against a panel of non-small-cell lung cancer lines. Second, in the NCI60 panel of cell lines drawn from nine different types of cancer, three HIV protease inhibitors inhibited cell growth. Nelfinavir was again most potent, showing activity against all cancer types tested. In mice, nelfinavir inhibited the growth of two types of lung cancers.
"We're not convinced that Akt is the critical target of nelfinavir therapy because the effect on that pathway is transient," said Dr. Dennis. "But we were able to show with biomarkers that this treatment impacts tumor growth, in part by inducing apoptosis," the normal process of programmed cell death to eliminate old or damaged cells.
The scientists made an interesting discovery about nelfinavir. When tumor cells in mice were treated with this protease inhibitor, some cells that did not die by apoptosis still died by a nonapoptotic process. Drug treatment put stress on the endoplasmic reticulum (ER), the part of a cell where proteins are made, which triggered a process known as autophagy in which cells under stress digest themselves.
ER stress and autophagy are cellular processes that are gaining importance in cancer research because researchers suspect that impaired autophagy may contribute to cancer development. Markers of ER stress and autophagy will be useful for studying nelfinavir in clinical trials for cancer patients.
"The need for expedited development of effective cancer therapies is critical," said Dr. Dennis. "Repositioning drugs that are already FDA-approved for use in patients could greatly accelerate the development of new cancer therapies. Our data suggest that, given its wide spectrum of activity, nelfinavir could be successfully repositioned as a cancer therapeutic."
— Addison Greenwood