VARI Researchers Slow Tumor Growth

March 28, 2008
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Researchers at the Van Andel Research Institute have discovered a way to slow the growth of a common form of kidney cancer in an experimental model of human tumors in a mouse. They found that using the lethal bacterium that causes anthrax blocked a specific signaling pathway in tumor cells that stimulates tumor growth.

The kidney cancer study was carried out by VARI’s Laboratory of Cancer Genetics under the leadership of distinguished scientific investigator Bin Tean Teh. The study was published earlier this year in the Cancer Research publication and includes scientific contributions from VARI’s Laboratory of Cancer and Developmental Cell Biology, headed by Senior Scientific Investigator Nicholas S. Duesbery, and VARI’s Laboratory of Analytical, Cellular and Molecular Microscopy, headed by distinguished scientific investigator James Resau.

Dan Huang, a postdoctoral fellow at VARI, was lead author of the study.

Clear cell renal carcinoma — the cancer targeted in the study — is the most common type of kidney cancer, accounting for about 80 percent of all kidney tumors, Teh pointed out.

Several years ago, Duesbery’s lab had shown that the lethal toxin known as LEPIMAT kills skin cancer, or melanoma, by inhibiting tumor growth and vascularization. Vascularization of tumors is usually a prelude to more rapid growth — and often to metastasis. VARI was the first to discover LEPIMAT’s use against melanoma and has been working on developing LEPIMAT as a therapeutic agent for advanced melanoma for some time, Duesbery said. He said the institute is recruiting partners and resources to enter into clinical trials.

“Bin’s discovery that the same pathway that we were attacking in melanoma was also   active in kidney cancer was a major step forward, I think, in understanding how kidney cancer grows,” Duesbery remarked. “It was a natural extension of his work to take the compound we had been developing and try it on kidney cancer.”

Teh said the study was the first time LEPIMAT had been used in a study of kidney cancer. Like any other part of the human body, tumors need blood to survive, Teh pointed out. Blood vessels in tumors give the cells what they need to grow and multiply; by decreasing blood supply, LEPIMAT makes it difficult for tumor cells to survive.

There are other drugs that have come to the market in the last 18 months that, like LEPIMAT, block blood vessel formation inside tumors, Duesbery noted. What’s exciting about LEPIMAT in contrast to the others, he said, is that it has a slightly different mechanism of action, he said. The other drugs work on the principle of binding to or blocking the actions of growth factors that are released by the tumors that promote blood vessel formation. LEPIMAT works one step ahead of that: It actually blocks the release of those growth factors to the medium. It’s a different underlying mechanism but the end result is the same: It blocks the actions of the signals that promote formation of blood vessels. 

Tumor cells have to do a couple of things within the tumor: They must make more tumor cells, and they also have to stimulate blood supply to nourish the newly created tumor cells. The tumor cells stimulate blood supply by releasing vascular endothelial growth factor, or VEGF, to the surrounding environment, Duesbery explained.

It has been known for quite a while that the protein called mitogen-activated protein kinase, or MAPK, is important in promoting cell division. Previous studies by researchers elsewhere found that mutations of proteins in the MAPK pathway contributed to 20 percent of all human cancers, and that proteins in this pathway play a crucial role in tumor formation and spread, as well as in blood vessel formation. Teh said MAPK is highly expressed in the vast majority of kidney tumors, and its presence causes tumor cells to go into overdrive.

“The discovery that we’ve made since then, both in melanoma and now in kidney cancer, is that the same pathways also play an important role in promoting VEGF release,” he continued.

The protein the institute is targeting is actually “upstream” of MAPK; it’s a protein called MKK, which turns MAPK on and off. The LEPIMAT compound gains entry into cells and blocks MKK activation. Knocking out MKK prevents MAPK from being turned on, which, in turn, keeps vascular growth factor from being released.

“Melanoma actually has a large number of genetic mutations in pathways that activate the MKK-MAPK pathway. That’s why it’s a really good target, because we can knock out this pathway. We see more than an 80 percent drop in VEGF that’s being released, and the rate at which cells divide decreases, as well,” Duesbery said. “So, really, it’s a two-pronged effect: We get them to stop growing, but at the same time, we block their ability to recruit new blood vessels and supply the tumor with more food.” 

The advantage of LEPIMAT is that, either on its own or in combination with the other inhibitors, VARI has potentially uncovered a much more effective way of blocking the signals from being released and from stimulating blood vessels to form, Duesbery explained.    

Just as one antibiotic would be very effective in killing off 99.9 percent of bacteria in an infection, using two antibiotics that work in different ways could kill off an even greater proportion of the bacteria that’s there, he said. 

“In the same sense, two different inhibitors both targeting vascularization but hitting different mechanisms or steps in a pathway can be a much more effective therapy,” Duesbery added. “Our compound is a novel mechanism for inhibiting blood vessel formation.”

The growth of certain types of tumors, such as kidney tumors and skin cancer, are highly dependent on vascularization, Teh pointed out. Published research has shown the same to be true for cancers such as Kaposi’s sarcoma, fibrosarcoma, glioblastoma and colorectal adenocarcinoma. 

LEPIMAT is a trademarked pharmaceutical of VAI Innovations LLC. HQX

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