Informing on inflammation
by Kelsey Kaustinen  |  Email the author


ANN ARBOR, Mich.—Cancer recurrence is one of the greatest fears of cancer patients next to metastasis, and it proves especially worrisome when some cancers seem to be treatment-resistant from the very beginning. This is seen often in patients diagnosed with HER2 breast cancer, because despite the effectiveness of cancer treatments such as Herceptin, almost half of all HER2 cancers prove resistant to the treatment from the onset, and nearly all develop some resistance over time.  
Some of the latest research from the University of Michigan Comprehensive Cancer Center indicates that the activation of an inflammatory pathway is to blame, a pathway that involves interleukin-6 (IL-6), a protein known to contribute to the inflammation typical of rheumatoid arthritis. In mouse studies, the researchers were able to prove that inhibiting the cytokine can overcome the tumors' resistance.  
"It already was known that the most common molecular change associated with developing resistance to HER2-targeted therapy was the down-regulation of a tumor-suppressant gene called PTEN," says Dr. Max S. Wicha, Distinguished Professor of Oncology and director of the U-M Comprehensive Cancer Center. "That had been already described, so in our paper we genetically engineered cells that were sensitive to Herceptin by knocking down the PTEN gene. And that's how we discovered that when we knocked down the PTEN gene, just like in human cancers that become resistant, the cancers became completely resistant to trastuzumab (Herceptin) in mice. And these cancers then began produce tremendous amounts of the cytokine IL-6."  
IL-6 turned out to also be responsible for regulating cancer stem cells, says Wicha, who is senior author for the study. The cytokine was found to fuel the cancer stem cells, making the tumors even more aggressive. Fortunately, not only does IL-6 interact with a receptor, which can be blocked, an antibody already exists to block the receptor. The antibody tocilizumab, which is owned by Roche, was originally developed (and approved by the U.S. Food and Drug Administration) to treat rheumatoid arthritis. Wicha notes that the antibody has proven to be very well tolerated, with few side effects. Mice that were treated with both the inhibitor and Herceptin immediately after the onset of cancer never developed Herceptin resistance.
"So what we found was that tumors that are resistant to HER2-blocking agents that activate IL-6 are very inhibited by the blocker of the IL-6 receptor, and it knocks down the cancer stem cells," says Wicha. "So we now have a non-toxic therapy that we think might be very valuable to treat trastuzumab-resistant breast cancers."  
Wicha says that it appears the inflammatory pathway can be either turned on naturally or as a defensive reaction to cancer treatments. Some cancers, he notes, have endogenous resistance, a lack of the PTEN gene, from the very beginning, and some have IL-6 activated from the onset as well, while others lose the PTEN gene as they are treated with Herceptin. The models, Wicha says, show that the IL-6 receptor "is actually involved in both acquired and de-novo resistance…and there's also data in humans that some of the human tumors have PTEN deleted right from the beginning, and others develop PTEN-silencing as the tumor progresses."  
"There is evidence that patients with a lot of IL-6 tend to do poorly. What we found now is that in many of the Herceptin-resistant breast cancers, the IL-6 inflammation loop is driving the cancer stem cell," lead study author Dr. Hasan Korkaya, research assistant professor of internal medicine at the U-M Medical School, said in a press release.  
Moving forward, the researchers are developing a clinical trial to test the IL-6 inhibitor with Herceptin, a trial that will most likely begin in 2013.
"We're currently in conversation with Roche, they're very interested in our research and we're working with them to design a clinical trial that will be using the IL-6 receptor antibody in combination with a HER2- targeted agent to try to overcome resistance to these HER2-targeted agents," says Wicha. "So hopefully we're going to be moving this into the clinic very soon."  
Patients with higher levels of IL-6 in their serum seemed to do much worse than those with lower levels, Wicha notes, and as such the researchers will be using IL-6 as a biomarker in their clinical trials. Additionally, he adds, the inhibition of IL-6 could also serve to deal with the issue of cancer cachexia, or weight loss. IL-6, Wicha notes, has already been established as a main mediator of tumor cachexia, and the team found that when given the IL-6 inhibitor, the mice used in the study "started putting on weight, they looked better." They will be examining this further in the clinical trials as well.  
Wicha adds that IL-6 seems to be involved in a variety of cancers, including head and neck, liver and pancreas cancers.
The study, "Activation of an IL6 Inflammatory Loop Mediates Trastuzumab Resistance in HER2+ Breast Cancer by Expanding the Cancer Stem Cell Population," was published online by Molecular Cell, and will appear in the Aug. 24 issue of the same publication.  

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