Recent Publications by VICC Researchers

March 12, 2013

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 2012:

New clues to treating melanoma

New therapies for melanoma, like the drug vemurafenib (Zelboraf), have increased survival among patients with a specific mutation the BRAF gene. However, many patients treated with the vemurafenib develop secondary skin cancers. In the Jan. 19 New England Journal of Medicine, Vanderbilt-Ingram investigators Igor Puzanov, M.D., and Jeffrey Sosman, M.D., and colleagues from 12 other cancer centers reported about 60 percent of these secondary skin cancers harbored mutations in a RAS gene.  While vemurafenib did not initiate or promote cancer development, it accelerated growth of existing lesions that harbored RAS mutations. MEK inhibitor drugs blocked the growth of these tumors, suggesting that a combination therapy of BRAF and MEK inhibitors might be beneficial for melanoma patients. In the Nov. 1 New England Journal of Medicine, Puzanov, Sosman and colleagues reported the results of a Phase I/II study using a combination therapy of a different BRAF inhibitor (dabrafenib) and a MEK inhibitor, showing that combination therapy delays resistance, but does not stop it completely. However, combination therapy reduced side effects (skin toxicity and secondary skin cancers) compared to dabrafenib alone.

Study links genes to resistance to breast cancer chemotherapy

A study by Justin Balko, Pharm.D., Ph.D., Carlos Arteaga, M.D., and colleagues has identified a gene expression pattern that may explain why chemotherapy prior to surgery isn’t effective against some tumors. They found that low concentrations of dual-specificity protein phosphatase 4 (DUSP4) is strongly correlated with faster tumor cell growth following neoadjuvant chemotherapy and also with a type of breast cancer known as basal-like breast cancer (BLBC). Cancer cells with DUSP4 experimentally deleted showed a much lower response to chemotherapy. In mice, a combination of chemotherapy (docetaxel) with a MEK inhibitor drug was much more effective than docetaxel alone at eliminating the mouse tumors. The findings, published in the July 2012 Nature Medicine, support exploratory clinical trials combining chemotherapy and MEK inhibitors in patients with DUSP-deficient basal-like breast cancer.

Method may refine personalized trials for cancer therapy

A new tool to observe cell behavior has revealed surprising clues about how cancer cells respond to therapy, and may offer a way to further refine personalized cancer treatments. The approach, developed by Vito Quaranta, M.D., and colleagues shows that erlotinib — a targeted therapy that acts on a growth factor receptor mutated in some lung, brain and other cancers — doesn’t simply kill tumor cells as was previously assumed. The drug also causes some tumor cells to go into a non-dividing (quiescent) state or to slow down their rate of division. This variability in cell response to the drug may be involved in cancer recurrence and drug resistance, the authors suggest. The new tool, reported Aug. 12 in Nature Methods, may offer ways to improve personalized cancer therapy by predicting tumor response and testing combinations of targeted therapies in an individual patient’s tumor.

Vitamin E intake linked to liver cancer risk

Liver cancer is the third most common cause of cancer mortality in the world. Approximately 85 percent of liver cancers occur in developing nations, with 54 percent in China alone. Vitamin E is a fat-soluble vitamin which is considered an antioxidant, and studies have suggested that vitamin E may prevent DNA damage. An international team of researchers, including Xiao-Ou Shu, M.D., Ph.D., and colleagues at Vanderbilt-Ingram, analyzed data from a total of 132,837 individuals in China enrolled in the Shanghai Women’s Health Study or the Shanghai Men’s Health Study, two population-based cohort studies jointly conducted by the Shanghai Cancer Institute and Vanderbilt University. The results, published July 17 in the Journal of the National Cancer Institute, revealed that high consumption of vitamin E – either from diet or vitamin supplements – was associated with lower risk of liver cancer.

Study tracks how gene may promote lung cancer tumors

Vanderbilt-Ingram Cancer Center researchers have identified how one of the genes most commonly mutated in lung cancer may promote such tumors. Jin Chen, M.D., Ph.D., and colleagues found that the protein encoded by this gene, called EPHA3, normally inhibits tumor formation, and that loss or mutation of the gene – as often happens in lung cancer – diminishes this tumor-suppressive effect, potentially sparking the formation of lung cancer. The findings, published July 24 in the Journal of the National Cancer Institute, suggest that mutations in EPHA3 may be important drivers of a significant fraction of lung cancers – and could offer direction for personalizing cancer treatments and development of new therapies.

Proteins may point way to new prostate cancer drug targets

The gene encoding NKX3.1, a transcription factor and tumor suppressor protein, is one of the most commonly deleted genes in human prostate cancer and is typically lost early in the disease process. Sarki Abdulkadir, M.D., Ph.D., and colleagues recently identified 282 genes regulated by NKX3.1. Using bioinformatics tools, they found that a quarter of the NKX3.1-regulated genes are also bound by a “famous” oncogene called Myc (which, like NKX3.1, is also a transcription factor), in many cases with NKX repressing expression and Myc activating expression. In mice with NKX3.1 deleted and Myc overexpressed in prostate cells, tumors progressed to advanced cancer. The findings, reported in the (date) issue of the Journal of Clinical Investigation, demonstrate that these two proteins with opposing cellular actions regulate the same set of genes in prostate cancer, pointing to potential new drug targets and prognostic markers for the disease.

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