A large-scale survey of genetic changes in lung tumors has identified 26 frequently altered genes in the most common form of the disease, lung adenocarcinoma. The discovery, reported in the October 23 Nature, increases the number of genes associated with lung cancer and expands the base of knowledge about the genetics of this deadly disease.
The Tumor Sequencing Project, a group of academic researchers funded by the National Human Genome Research Institute, analyzed more than 600 genes in 188 lung tumors for noninherited mutations as well as gains and losses of DNA. Their integrated analysis supports the view of cancer as a disease in which core biological pathways may be altered by various types of changes in multiple genes.
For instance, more than two-thirds of the tumors had at least one mutation affecting the MAPK pathway. Lung cancer patients with these changes may benefit from drugs that affect this pathway, the researchers suggest, noting that compounds called MEK inhibitors have produced promising results in mouse models of colon cancer.
The findings complement other large-scale genomic studies, including an analysis of glioblastoma brain tumors by The Cancer Genome Atlas (TCGA) project that appears in the same issue (the findings were published online in September).
In both the lung and brain studies, new mutations were identified in some of the same cancer-causing genes, noted Dr. Matthew Myerson of the Dana-Farber Cancer Institute, who was a leader of both studies. The overlap suggests that despite the diversity of genetic changes in cancer, some targeted therapies will be effective in multiple tumor types, he said in a conference call with reporters. Current examples of such drugs include imatinib (Gleevec) and cetuximab (Erbitux).
Bevacizumab Tested as Imaging Agent
Combining a low dose of the anti-angiogenesis agent bevacizumab (Avastin) with a radioactive tracer may be an effective method for imaging tumors, according to findings presented October 22 at an international conference. In the study, Dr. Zheng Jim Wang and colleagues from University of Texas Health Science Center at San Antonio and MPI Research, Inc., used bevacizumab with the radioactive tracer copper-64 (64Cu) attached to it in mouse models of breast, lung, and pancreatic cancer.
The resulting tumor images, Dr. Wang reported at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Geneva, Switzerland, were superior to those obtained a day before in the same mice using what they said is considered "the gold standard" for tumor imaging - PET scanning with the imaging probe 18FDG. In addition, he noted, by using this combination as an imaging agent, the research team was able to detect tumors that were smaller and of an earlier stage than was possible with 18FDG.
The one-time administration of the compound uses a dose of bevacizumab that is 2.5 to 11.5 times less than the typical therapeutic dose given to patients. "Although we haven't pursued the dose-contrast correlation study yet, we believe there still is some room to decrease the [bevacizumab] dose and still achieve satisfying results for tumor detection," explained Dr. Wang.
Bevacizumab, which is approved in the United States for the treatment of advanced colorectal, breast, and lung cancers, targets vascular endothelial growth factor (VEGF), an important signaling protein that helps tumors develop the blood vessels needed to support their growth.
Stress, Depression Linked to Changes in Ovarian Tumors
Researchers have found that patients with ovarian cancer who experienced symptoms of depression and stress had elevated levels of an enzyme associated with the spread of cancer in macrophages, influential cells in the tumor microenvironment. The enzyme, MMP9, is a matrix metalloproteinase, which can induce cancer cells to invade and metastasize. The study included 56 women, and the findings appeared in the November 1 Clinical Cancer Research.
Dr. Susan K. Lutgendorf of the University of Iowa and her colleagues found that depressive symptoms, chronic stress, and low social support were strongly associated with increased levels of MMP9 in tumor-associated macrophages. Conversely, patients who had higher levels of social support had lower levels of MMP9 and VEGF, a growth factor that promotes the development of tumor blood vessels.
To look more closely at the mechanism by which these signals are elevated, the researchers exposed macrophages in vitro to hormones released during depression and stress, norepinephrine and cortisol, at concentrations similar to those found in vivo when a person is under stress. They found that this exposure increased production of MMP9 in the cells.
"These findings provide a new understanding of biobehavioral influences on the tumor microenvironment and may have implications for patient outcome and targeted pharmacologic and/or behavioral interventions for ovarian cancer patients," the researchers wrote.