Some of the latest research from the University of MichiganComprehensive Cancer Center indicates that the activation of an inflammatorypathway is to blame, a pathway that involves interleukin-6 (IL-6), a proteinknown to contribute to the inflammation typical of rheumatoid arthritis. Inmouse studies, the researchers were able to prove that inhibiting the cytokinecan overcome the tumors' resistance.
"It already was known that the most common molecular changeassociated with developing resistance to HER2-targeted therapy was thedown-regulation of a tumor-suppressant gene called PTEN," says Dr. Max S.Wicha, Distinguished Professor of Oncology and director of the U-MComprehensive Cancer Center. "That had been already described, so in our paperwe genetically engineered cells that were sensitive to Herceptin by knockingdown the PTEN gene. And that's how we discovered that when we knocked down thePTEN gene, just like in human cancers that become resistant, the cancers becamecompletely resistant to trastuzumab (Herceptin) in mice. And these cancers thenbegan produce tremendous amounts of the cytokine IL-6."
IL-6 turned out to also be responsible for regulating cancerstem cells, says Wicha, who is senior author for the study. The cytokine wasfound 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 theantibody has proven to be very well tolerated, with few side effects. Mice thatwere treated with both the inhibitor and Herceptin immediately after the onsetof cancer never developed Herceptin resistance.
"So what we found was that tumors that are resistant toHER2-blocking agents that activate IL-6 are very inhibited by the blocker ofthe IL-6 receptor, and it knocks down the cancer stem cells," says Wicha. "Sowe now have a non-toxic therapy that we think might be very valuable to treattrastuzumab-resistant breast cancers."
Wicha says that it appears the inflammatory pathway can beeither 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 acquiredand de-novo resistance…and there's alsodata in humans that some of the human tumors have PTEN deleted right from thebeginning, and others develop PTEN-silencing as the tumor progresses."
"There is evidence that patients with a lot of IL-6 tend todo poorly. What we found now is that in many of the Herceptin-resistant breastcancers, the IL-6 inflammation loop is driving the cancer stem cell," leadstudy author Dr. Hasan Korkaya, research assistant professor of internalmedicine at the U-M Medical School, said in a press release.
Moving forward, the researchers are developing a clinicaltrial to test the IL-6 inhibitor with Herceptin, a trial that will most likelybegin in 2013.
"We're currently in conversation with Roche, they're veryinterested in our research and we're working with them to design a clinicaltrial that will be using the IL-6 receptor antibody in combination with aHER2-targeted agent to try to overcome resistance to these HER2-targetedagents," says Wicha. "So hopefully we're going to be moving this into the clinicvery soon."
Patients with higher levels of IL-6 in their serum seemed todo much worse than those with lower levels, Wicha notes, and as such theresearchers 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 theissue of cancer cachexia, or weight loss. IL-6, Wicha notes, has already beenestablished as a main mediator of tumor cachexia, and the team found that whengiven the IL-6 inhibitor, the mice used in the study "started putting onweight, they looked better." They will be examining this further in theclinical trials as well.
Wicha adds that IL-6 seems to be involved in a variety ofcancers, including head and neck, liver and pancreas cancers.
The study, "Activation of an IL6 Inflammatory Loop MediatesTrastuzumab Resistance in HER2+ Breast Cancer by Expanding the Cancer Stem CellPopulation," was published online by MolecularCell, and will appear in the Aug. 24 issue of the same publication.
