Recent Publications by VICC Researchers

Vanderbilt-Ingram Cancer Center is committed to conducting innovative, high-impact, basic, translational and clinical research with the greatest potential for making a difference for cancer patients, today and in the future. Here’s a sampling of work published in peer-reviewed journals by Cancer Center investigators in 2011:

Study Snuffs Out Menthol Myths

People who smoke mentholated cigarettes are no more likely to develop lung cancer or to die from the disease than smokers of non-mentholated cigarettes, according to a study led by William Blot, Ph.D., and colleagues. The study, published in the March Journal of the National Cancer Institute, showed that, among people smoking 20 or more cigarettes a day, menthol smokers were approximately 12 times more likely to develop lung cancer than never-smokers, while non-menthol smokers were about 21 times more likely to have the disease. In addition, both white and black menthol smokers reported smoking fewer cigarettes per day than non-menthol smokers. There was no significant difference between menthol and non-menthol smokers in the likelihood of quitting smoking. The findings suggest that mentholated cigarettes are no more, and perhaps less, harmful than non-mentholated cigarettes.

Heart Protein’s Role in Colon Cancer

A protein critical in heart development may play a part in colon cancer progression and may be a therapeutic target for halting metastasis. In the October Journal of Clinical Investigation, Christopher Williams, M.D., Ph.D., Min Chang, M.D., and colleagues report that BVES (blood vessel endocardial substance) levels were very low in all stages of human colon cancer, in other types of epithelial cancers (including breast), and in several colorectal cancer cell lines. They found that a DNA region that controls gene expression was heavily modified (methylated), which silenced its expression – and that treating cells with a “demethylating” agent restored BVES expression. The findings suggest that treatment with agents to increase BVES levels might decrease aggressive behaviors of colorectal and many other epithelial cancers – which account for about 85 percent of cancers.

Six Subtypes Identified in Breast Cancer

In the July Journal of Clinical Investigation, Jennifer Pietenpol, Ph.D., and colleagues report the identification of six subtypes of “triple-negative breast cancer” (TNBC), an aggressive and difficult-to-treat form of breast cancer that accounts for 10 percent to 20 percent of all breast cancers. Using genomic data from publically available breast cancer data sets, they identified: two “basal-like” types involving cell cycle and DNA damage response genes; two “mesenchymal” types driven by genes involved in cell differentiation and growth factor pathways; an “immunomodulatory” group, driven by immune system genes; and a “luminal” subgroup driven by androgen (or “male” sex hormone) signaling. They also identified chemotherapies to which the different subtypes respond in cultured cells and animal tumor models. This information may help physicians determine appropriate therapies for patients with TNBC and also inform the discovery and development of new drugs to treat this aggressive cancer.

New Mode of Growth Factor Signaling

Increased expression or activity of the epidermal growth factor receptor (EGFR) is seen in many cancers. The growth factors (or ligands) that bind to EGFR have three recognized modes of signaling – autocrine, paracrine and juxtacrine. Robert Coffey, M.D., and colleagues have identified a new mode of EGFR ligand signaling via small (30-90nm) membrane-bound vesicles (exosomes) and dubbed this new signaling mode “extracrine.” They show that human breast and colorectal cancer cells release exosomes containing full-length, signaling-competent EGFR ligands. Exosomes containing the ligand amphiregulin increased invasiveness of breast cancer cells 4-fold over exosomes containing two other EGFR ligands (TGF-α and HB-EGF). The findings, published in the May Current Biology, suggest that this new signaling mode could have important implications for cancer invasion, metastasis and the tendency of cancer cells to cause changes to normal cells that surround them.

Breast Cancer Study Combines Therapies

Around 25 percent of breast cancers have increased expression of the HER2 receptor, which is associated with more aggressive tumors and a poorer prognosis. While HER2-targeted therapies like trastuzumab (Herceptin) and lapatinib (Tykerb) are effective in many women with HER2-positive breast tumors, the clinical response tends to be short-lived and tumors eventually become resistant. Two studies led by Carlos Arteaga, M.D., and reported in the Proceedings of the National Academy of Sciences (PNAS) in February and March suggest that upregulation of the HER3 receptor limits the effectiveness of two classes of targeted therapies (HER2- and PI3 kinase-targeted therapies) and that targeting HER3 together with these agents should improve their clinical utility. The findings suggest that combining targeted therapies might be required for maximum anti-tumor activity when treating HER2-positive breast cancers.

Lung Cancer Study Suggests Therapy Change

Patients with metastatic non-small cell lung cancers (NSCLCs) treated with tyrosine kinase inhibitors (TKIs) eventually develop resistance to these therapies. While some patients start responding again after a break in therapy, there has been no way to predict who will respond. In experiments with cells that were either sensitive or resistant to TKIs, William Pao, M.D., Ph.D., and colleagues found that drug-resistant cells grew more slowly than the drug-sensitive cells. They verified the relevance of the findings to human disease and, using mathematical models, predicted that using high-dose pulses of erlotinib (Tarceva) or a more potent TKI in conjunction with a continuous low-dose schedule could delay the establishment of drug resistance. The findings, published in the July Science Translational Medicine, suggest that altering the timing and dosages of certain therapies for NSCLC may help delay the onset of drug resistance.