Journal Watch

Vanderbilt-Ingram Cancer Center's mission is to conduct the innovative, high-impact basic, translational and clinical research with the greatest potential to make a difference for cancer patients. Here's a sampling of recent work published by center members:

Study Finds Treatment Paradox
A team led by Carlos Arteaga, M.D., reported a paradox in the treatment of advanced cancer – the link between a treatment-induced growth factor and the cancer's future spread. The findings may help explain why anti-tumor therapies often work only partially or not at all in advanced cancers and tumors progress after treatment. The investigators reported that radiation and chemotherapy increase circulating levels of the growth factor TGF-beta, circulating cancer cells, and tumor metastases in a mouse model of metastatic breast cancer. Blocking TGF-beta in the model prevented tumor metastases, suggesting that TGFbeta inhibitors – some of which are currently in early stage clinical trials – may be useful in combination with primary therapies. The work appeared in the Journal of Clinical Investigation.

Team Identifies Culprit in Metastasis
Researchers at Vanderbilt have identified a molecular mechanism at the hub of numerous cell behaviors — and possibly at the root of metastasis. Albert Reynolds, Ph.D., and colleagues have identified a protein at the center of it all, p120-catenin, and described the mechanism it uses to coordinate cell growth, motility and adhesion. Reynolds first discovered p120 in 1989 and found that the protein is a key regulator of cadherin function and plays a critical role in cell-cell adhesion. The current study continues to build the case that p120 participates in processes that govern whether a cancer cell becomes metastatic, and provides a mechanistic link between the behaviors that are disrupted in metastatic cells — something that has been suspected since p120's discovery. The work appeared in Cell.

Model Could Help Doctors Pick Best Treatment for Lung Cancer
Some patients with non-small cell lung cancer (NSCLC) respond to treatment with a class of drugs that block cell communication and growth (tyrosine kinase inhibitors). However, physicians don't have a good way to predict just who will respond well. Now David Carbone, M.D., Ph.D., and colleagues have developed a model that predicts survival of patients with NSCLC after treatment with gefitinib or erlotinib, two of these drugs. The model uses mass spectrometry "signatures" of proteins found in the bloodstream of patients before their treatment to categorize patients by "good" and "poor" outcomes. In one of the validation groups, the "good" outcome patients had a median survival of 306 days, compared to 107 days for the "poor" group. This work, which appeared in the Journal of the National Cancer Institute, suggests that these so-called biomarkers could be used to select the most effective therapy.

Animal Model May Shed Light on Deadly Pancreas Cancer
Vanderbilt-Ingram Cancer Center researchers have developed a new animal model for pancreatic cancer that exhibits a high degree of similarity to human tumors. Results from a study of genetically engineered mice, published in the journal Genes and Development, suggest that the mice could provide new opportunities to investigate targeted chemotherapeutics and screening methods for one of the most deadly cancers. "Most cases are diagnosed at a late stage when it is incurable," said Hal Moses, M.D., professor of Cancer Biology and senior author on the study. Developing an animal model of pancreatic cancer is essential to identifying new treatment and screening options.

Trial Shows Promising Option for Advanced Cancer
Results of a multi-center clinical trial of the drug bevacizumab (Avastin) in patients with advanced, non-squamous, nonsmall cell lung cancer show it may help extend the lives of some patients. Alan Sandler, M.D., David Johnson, M.D., and colleagues reported in the New England Journal of Medicine data from a trial of nearly 900 patients with metastatic, non-squamous, nonsmall cell lung cancer (NSCLC). The patients had not received prior chemotherapy. Half received Avastin in addition to chemotherapy, and half got standard chemotherapy alone. Patients who received Avastin combined with chemotherapy lived, on average, about two months longer (12.3 months) than the group who only received chemotherapy (10.3 months). The findings show the first promising option in years for treating patients with this advanced and often deadly form of lung cancer.

Structure Identification Sheds Light on DNA Repair
Enzyme A team led by Brandt Eichman, Ph.D., has identified the structure of an enzyme that removes certain damaged DNA bases, the single "letters" that make up a strand of DNA. Having the structure reveals clues about how this enzyme works and could be helpful in understanding cancer because exposure to carcinogens can cause this kind of damage. This enzyme, part of the cell's DNA repair system, reverses the damage and returns the DNA to its "undamaged" state. In addition, agents that produce this type of DNA damage are used in some chemotherapy. So, understanding this type of damage could help protect against carcinogens, and might help improve anti-cancer drugs that use these agents. The work was reported in The EMBO Journal.

New role for DNA-binding proteins
In the April 15 issue of Genes& Development, Stephen Brandt, M.D., and colleagues report that single-stranded DNA-binding proteins (SSBPs), which normally act to keep DNA "unraveled" during transcription, also regulate the abundance of protein components of DNA-binding complexes that drive red blood cell differentiation. The results also suggest that altered expression of SSBPs, which has been observed in several cancer types including certain leukemias, may contribute to tumorigenesis by disrupting the normal balance of these DNA-binding complexes.