VARI Using 'Novel' Cancer Study

December 10, 2004
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GRAND RAPIDS — A postdoctoral fellow with the Van Andel Research Institute is several months into a research project that’s employing new technology developed by VARI to study multiple myeloma, a blood-borne cancer that causes bones to deteriorate.

With a $50,000 fellowship grant from the Multiple Myeloma Foundation, Jennifer Bromberg-White, Ph.D., is pursuing a one-year study designed to identify the reasons why many multiple myeloma patients are resistant to melphalan, the primary drug that’s been used to combat the disease for more than 40 years.

Through previous genomic profiling, VARI researchers identified a number of the melphalan-resistant genes and developed what’s called an “avian-based retroviral delivery system” that targets the resistant tumor cells and renders their protein inactive.

“It induces the genes to be degraded inside the cell so that the protein never gets made,” Bromberg-White explained.

By disabling the resistant genes, non-resistant genes in cells could be treated more effectively because the patient’s sensitivity to melphalan would be restored, she said. About 60 percent of all multiple myeloma patients respond to melphalan treatment but eventually become resistant to it, Bromberg-White said.

“If we can prevent patients from becoming resistant then we can treat them longer with the drug and, hopefully, give them a better chance of survival and have longer survival rates.”

Presently, more than 40,000 Americans are living with multiple myeloma and more than 11,000 typically die of the disease each year, usually within three years of diagnosis, according to the American Cancer Society.

Bromberg-White said VARI’s multiple myeloma laboratory has been working with area hospitals to get multiple myeloma patient samples, and those genetic profiles are consistently analyzed at the lab.

“We have an ongoing analysis of genes to target and the list is long. An easy way to pick a good target is to determine whether it’s a drug-able target. If you can create a drug to that, then that’s something that could be added into the treatment along with melphalan.”

Getting the retroviral delivery system up and running was Bromberg-White’s first order of business when she joined VARI in 2002. Her lab is the first at VARI to employ the system, though it will be used in other cancer research studies at the institute, as well, she said.

The use of retroviruses to target genes isn’t brand new but the avian-based retroviral idea is a recent breakthrough in science, Bromberg-White said.

“The avian retrovirus existed before and we just modified it for our own purposes. We decided to use an avian system because an avian (bird) virus would not infect human cells; you can’t catch viruses from a bird,” she explained. “This is a quick way to get something inside cells and it has high specificity for delivery. We can target it just to the cells we’re interested in.”

She said the multiple myeloma laboratory is currently in the process of infecting cells with the virus to see if they can knock out the genes they’re interested in and determine what it does to the melphalan resistance of cells. The next step will be injecting the cells into mice. Actual clinical trials are quite a ways down the road, she said.

Melphalan doesn’t have the greatest track record. It was developed in the ’60s as a treatment for multiple myeloma and most of the time it’s still the first course of action in treatment, she said. The five-year survival rate for multiple myeloma has remained at 28 percent for the past 20 years and only 3 percent of patients actually complete remission.

“That’s one of the main reasons we wanted to do the study. Melphalan doesn’t do a great job, but obviously nothing better has come along,” Bromberg-White acknowledged. “So our main goal is to try to either create an environment in the cells where we can prolong the treatment of melphalan or figure out a way to get around the resistance.”

It’s “absolutely possible” that in her research she could stumble upon or uncover something that could lead to the development of a drug more effective than melphalan.

“That’s another branch of our multi-level research laboratory that we focus on — not just trying to change a resistant phenotype, but also trying to develop other drugs that might work better.”

Bromberg-White is working under the guidance of Scientific Investigator Craig P. Webb, Ph.D., head of VARI’s Laboratory of Tumor Metastasis and Angiogenesis.    

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