miércoles, 17 de octubre de 2012

HIV Drug Blocks Growth of HER2-Positive Breast Cancer Cells ► NCI Cancer Bulletin for October 16, 2012 - National Cancer Institute

NCI Cancer Bulletin for October 16, 2012 - National Cancer Institute

HIV Drug Blocks Growth of HER2-Positive Breast Cancer Cells

Nelfinavir, a drug used to treat people infected with HIV, appears to halt the growth of HER2-positive breast cancer cells. Researchers led by Dr. Joong Sup Shim of the Johns Hopkins School of Medicine showed that, in the laboratory, doses of nelfinavir used to safely treat people infected with HIV inhibited the growth of drug-resistant HER2-positive breast cancer cells. The study appeared October 5 in the Journal of the National Cancer Institute.
Although several drugs are approved to treat HER2-positive breast cancers, tumors often develop resistance to these drugs, and new treatments are needed.
The researchers exposed seven genetically characterized breast cancer cell lines to drugs cataloged in the Johns Hopkins Drug Library, including anticancer drugs and drugs used to treat other diseases. (The protein-coding genes in the cells had been sequenced to determine whether they had mutations known to drive cancer.)
After finding that nelfinavir selectively inhibited HER2-positive breast cancer cells, compared with HER2-negative cells, the researchers teased out how the drug might work in HER2-positive cells. They found that nelfinavir inhibits a protein called heat-shock protein 90 (HSP90). Heat-shock proteins act as “chaperones,” helping newly synthesized proteins to fold properly and stabilizing their structures. When the activity of HSP90 is blocked by nelfinavir, the proteins that it normally helps fold and stabilize may not work correctly.
HSP90 helps stabilize the HER2 protein and another protein in its signaling pathway called AKT. Therefore, blocking HSP90 activity may lead to the breakdown of HER2 and AKT or a decrease in their activity, explained the authors. This could slow or stop the growth of cancer cells that cannot function without abnormal HER2 signaling.
When the researchers tested nelfinavir in xenograft models of breast cancer, mice with HER2-positive tumors that were given nelfinavir had tumors less than half the size of those in mice that were not given the drug, and nelfinavir substantially reduced the levels of active HER2 (but not AKT) in the tumors. In cell-culture experiments, nelfinavir inhibited the growth of three HER2-positive cell lines that were resistant to the anti-HER2 drugs trastuzumab (Herceptin) or lapatinib (Tykerb).
The researchers hope that clinical trials will start soon. The rationale for clinical trials of nelfinavir is particularly strong for patients with resistance to the available anti-HER2 treatments, who have a poor prognosis, explained Dr. Jun O. Liu, the study’s senior author.
The advantage of using a drug already approved for another disease, he added, is that the drug can likely skip phase I trials and go straight into phase II trials if tested at a dose currently used in the clinic. Another drug the research team found using this screening process, an antifungal/antibiotic called itraconazole, which inhibits tumor blood-vessel formation, leapt directly into phase II testing in cancer patients, he noted. (See the trial details here, here, and here.)
This research was supported by grants from the National Institutes of Health (CA122814, R01AI065983, and UL1 RR 025005).

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