NCI Cancer Bulletin: A Trusted Source for Cancer Research NewsNCI Cancer Bulletin: A Trusted Source for Cancer Research News
May 11, 2004 • Volume 1 / Number 19 E-Mail This Document  |  Download PDF  |  Bulletin Archive/Search  |  Subscribe

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Cancer Research HighlightsCancer Research Highlights

Statins Don't Increase Breast Carcinoma Risk, Study Says

Use of popular cholesterol-lowering drugs called statins does not increase post-menopausal women's risk of breast cancer, according to the results of a new NCI-funded study. Published in an early, online release of the June 1 issue of Cancer, the population-based, case-control study compared 975 women ages 65-79 diagnosed with breast carcinoma with 1,007 women without breast carcinoma. Statin use - whether extended use or a single period of use lasting at least six months - did not appear to increase breast carcinoma risk. On the contrary, regular use for more than five years was associated with a decrease in risk.

The 975 women were identified via a western Washington State cancer registry that is also part of NCI's Surveillance, Epidemiology, and End Results (SEER) program. All participants underwent in-person interviews, including the collection of a detailed medication usage inventory. Statin use has increased dramatically in recent years, explained lead author Dr. Denise Boudreau from the Center for Health Studies of the Group Health Cooperative in Seattle, Wash. In fact, the two top-selling drugs in the United States last year - Lipitor and Zocor - were statins, according to IMS Health.

"The increasing trend of statin use is likely to continue," the authors concluded, because of factors such as the aging population and expanded indications for primary prevention of coronary heart disease. "The current study results both provide reassurance concerning the safety of statin use among older women and support the emerging evidence that statins may have a chemopreventive action on breast carcinoma risk."

New Drug for Renal Cancer to Enter Phase I Trials

A new drug with selectivity for renal cell carcinoma may be in the offing in the next few years.

NCI scientists have been developing aminoflavone (AF) as a possible chemotherapy drug. AF is a synthetic compound related to natural plant chemicals called flavonoids. In the April 2004 Journal of Urology, the NCI team reports that AF has antitumor activity in animal models of renal cancer, with potent antiproliferative activity in certain renal cancer cell cultures, as well as in some cell strains, or explants, derived from patients' renal tumors.

"That AF worked in renal tumor explants, which are closer to tumors in people than cell cultures, is promising," said Dr. Edward Sausville, associate director of NCI's Developmental Therapeutics Program (DTP), who directed the research team.

AF exhibited selective reactivity for certain cell cultures or strains because those cells, like normal cells, were unable to metabolize the agent. "This means AF may kill tumor cells without destroying bone marrow and having other toxic effects," explained Dr. Sausville.

"Those tumor cells that metabolized the drug - which included a number of papillary renal cell carcinomas - self-destructed," said Dr. Sausville. DTP is producing more AF so the compound can enter phase I clinical trials in approximately six months.

If the drug works in humans, clinicians could feasibly do a biopsy or fine needle aspiration on a renal tumor and test the cells to see if they metabolize AF. "We could select patients who have the greatest likelihood of benefiting," said Dr. Sausville.

New Method Allows In Vivo Imaging of Drug Targets

Dr. Peter M. Smith-Jones and colleagues at Memorial Sloan-Kettering Cancer Center have developed a new technique that allows scientists to directly visualize the molecular effects of a drug in vivo, as reported in an advance online publication in Nature Biotechnology on May 9. In principle, this technique may be adapted for use with other drugs and can provide researchers with information on the mechanism of drug action, as well as yield pharmacological data on the correct dosage and schedule for a molecularly targeted drug.

The researchers studied the effects of 17-AAG, a derivative of the antibiotic geldanamycin, on the receptor tyrosine kinase HER2, which is a validated protein target for anticancer drugs in certain breast cancers. The imaging used positron emission tomography (PET) scanning that was based on the use of the radionuclide-labeled antibody trastuzumab (Herceptin) to target and label HER2. They could then visualize the changes in levels of HER2 in response to 17-AAG.

Compounds such as 17-AAG and geldanamycin indirectly affect the levels of HER2 by inhibiting heat shock protein 90 (Hsp90) - a chaperone protein that is required for the maturation and stability of certain key signaling proteins including HER2. Inhibition of Hsp90 results in antitumor activity caused by the degradation of HER2.

"This technique may be used to image the pharmacodynamic effects of antireceptor antibodies and tyrosine kinase inhibitors as well as Hsp90 inhibitors," conclude the authors of the report, regarding the applicability of this technique.

New Studies of BRCA1 Explain Its Role in Causing Cancer

Two new studies, published in advance of their print publication on the Nature Structural and Molecular Biology Web site on May 9, provide insight into the molecular mechanisms for how mutations in the tumor suppressor gene actually lead to cancer. Mutations in the BRCA1 gene are responsible for most cases of inherited, early-onset breast cancers.

The studies use X-ray crystallography to determine the molecular structure of the highly conserved BRCA1 C-terminal (BRCT) domain that consists of a tandem repeat of two highly similar subdomains. These BRCT tandem repeats function in the recognition and binding of BRCA1 with other proteins. The repeats recognize specific phosphoproteins, which are proteins that possess a phosphorylated serine or threonine amino acid. Phosphorylation is a common way for cells to regulate the interaction of proteins.

The first paper, by Dr. Michael B. Yaffe and colleagues from Massachusetts Institute of Technology and the UK National Institute for Medical Research, reports the structure of the BRCT domain with a peptide derived from the BACH1 protein, a known binding partner of BRCA1.

The second paper, by Dr. J. N. Mark Glover and colleagues at the University of Alberta, further elucidates the molecular and chemical nature of the recognition of phosphorylated proteins by the BRCT repeats.

Both reports show that the mutations abolish the ability of BRCA to recognize and bind to phosphorylated proteins, which disrupt the role of the protein in homologous recombination and DNA repair and lead to elevated cancer risk.