By bypassing a well-known gene implicated in almost one-third of all cancers and instead focusing on the protein activated by the gene, Dr. Christopher Counter and colleagues at the Duke University Medical Center have identified IL6 as a new target in the battle against Ras-induced cancers.
The ras gene, known as an oncogene when it is in this mutated state, has been implicated in several different cancers, including those of the pancreas and lungs. To date, efforts at blocking or turning off ras have proven ineffective. Pancreatic cancer has been shown to have the strongest link to the ras oncogene, and it is also one of the hardest cancers to treat, with few patients alive five years after diagnosis, researchers said.
Ras is a key intracellular messenger protein that directs, among other things, cell growth and proliferation. Over-expression of the Ras oncogene, or of its growth-promoting pathway, is an integral step in the development of a number of human cancers, particularly pancreatic and lung cancer. Unfortunately, though, attempts to target Ras for inhibition in a clinical setting have proved unsuccessful.
"We knew Ras was really important for cancer, but time after time it defied attempts to be inhibited in the clinic. So we decided, why not go after something that you can make a drug against that Ras activates"" explains Dr. Counter. Dr. Counter and colleagues sought to identify other proteins that are secreted when Ras is activated, and evaluate them as potential therapeutic candidates. One factor, in particular, is receiving a lot attention.
Interleukin-6 (IL6) is an inflammatory cytokine (growth factor) that stimulates the immune system in response to injury. Dr. Counter’s team has demonstrated that Ras induces the secretion of IL6 in a number of different cell types. The scientists then showed that IL6 promotes tumorigenesis by encouraging new blood vessel growth.
Dr. Counter and colleagues were able to successfully fight tumor formation in a preclinical model by suppressing IL6 activity. While further research is needed to determine the effectiveness of IL6 targeted cancer therapies, these initial results are encouraging. "Targeting secreted proteins that Ras activates has opened the door to inhibit the oncogenic signal of Ras via druggable proteins," states Dr. Counter.
“IL-6 was like the gas pedal driving the growth of tumors,” Counter said. “No gas, no growth, which is exactly what we saw when we inhibited IL-6 in tumors.”
A phase II trial is underway testing a monoclonal antibody against IL-6 for patients with multiple myeloma, a cancer that depends on IL-6 but is not known to have a connection to the ras oncogene. If the results of this trial are positive, studies might begin in ras-dependent cancers. Counter’s group is actively pursuing the idea that such an antibody may inhibit pancreatic cancer growth in mouse models.
Source: Cold Spring Harbor Laboratory
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