Oct. 11, 2012 After screening more than 2,300 drugs for their ability to halt the growth of breast cancer cells, Johns Hopkins researchers have discovered that the anti-HIV drug nelfinavir slows the progress of HER2-positive tumor cells, even if they are resistant to other breast cancer drugs.
In a report on the discovery published online Oct. 5 in the Journal of the National Cancer Institute, the investigators also say nelfinavir worked at concentrations already approved by the U.S. Food and Drug Administration. So-called HER2-positive breast cancers, which contain the protein HER2 and comprise 25 to 30 percent of cases, are more aggressive and less responsive to hormone treatments than HER2-negative cancers, a status that has fueled the search for better drug therapies and especially for ways to speed up the search by "repurposing" drugs already on the market.
"New drug development, beginning from scratch, is extremely expensive and time-consuming, taking an estimated $1 billion and more than 10 years to get each new compound to market," says Jun O. Liu, Ph.D., professor of pharmacology and molecular sciences at the Johns Hopkins University School of Medicine. "An existing drug has already passed most of the costly safety and regulatory hurdles," says Liu, who has worked on "repurposing" them for almost a decade.
To speed up drug discovery, Liu and his colleagues created the Johns Hopkins Drug Library, which currently includes nearly 2,900 drugs, most of which are FDA-approved. All have passed through phase I clinical trials to test their dosing safety.
In the new study, Liu and his team began with breast cancer cells from two patients, then tested all of the drugs in the library for their ability to stop cells from multiplying. Seventy of the best performers were selected for round two, in which they tested cells from seven patients, each genetically different, to see which drugs worked best.
Five of these drugs were selected for their ability to stop or slow the growth of HER2-positive cells. One of the five, nelfinavir, was selected for further testing because it appeared to work better than the others on HER2-positive cells and, says Liu, seemed to interfere with the protein HER2 itself. Nelfinavir was also already known to have a broad anti-cancer effect against melanoma, non-small-cell lung cancer and pancreatic cancer.
To see if nelfinavir worked in mice implanted with HER2-positive or HER2-negative human breast cancer cells, the team gave mice a fake drug or a human-dose equivalent of nelfinavir, then measured tumor size for a month. Nelfinavir slowed the growth of HER2-positive tumors, but had no effect on HER2-negative tumors in mice.
To see if nelfinavir could slow the growth of tumors that had become resistant to the commonly used breast cancer drugs trastuzumab and lapatinib, the researchers treated drug-resistant and non-drug-resistant cells growing in the lab with nelfinavir, trastuzumab or lapatinib. Only nelfinavir was able to prevent both drug-resistant and non-drug-resistant cells from growing.
When combating HIV, nelfinavir inhibits enzymes called proteases that break down proteins, and Liu's team wanted to know if nelfinavir uses that same mechanism to slow the growth of breast cancer cells. To test this, they gave nelfinavir to a wide variety of yeast cells, which are commonly used to study drug effects on genes because of the similarity between their cells and ours. Each type of yeast was genetically engineered to make less of a particular protein, making them more vulnerable to environmental stresses. They found that when yeast making less of the HSP90 protein were given the drug, the cells died, suggesting that nelfinavir interacts with HSP90, which is not a protease.
"This was interesting because we know that HSP90 also binds to HER2, and we now think that nelfinavir may be interfering with this interaction," says Liu. "This is a good starting point for clinical trials," he adds.
Other authors of the paper include Joong Sup Shim, Rajini Rao and Inkyu Han from The Johns Hopkins University; Kristin Beebe and Len Neckers from the National Cancer Institute; and Rita Nahta from Emory University School of Medicine.
This work was supported by grants from the National Cancer Institute (R01CA122814), the National Center for Research Resources (UL1 RR025005), Flight Attendant Medical Research Institute, the Commonwealth Foundation and the National Institute of Allergy and Infectious Diseases (R01AI065983).
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- J. S. Shim, R. Rao, K. Beebe, L. Neckers, I. Han, R. Nahta, J. O. Liu. Selective Inhibition of HER2-Positive Breast Cancer Cells by the HIV Protease Inhibitor Nelfinavir. JNCI Journal of the National Cancer Institute, 2012; DOI: 10.1093/jnci/djs396
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