Avtar Roopra

In a story of scientific discovery filled with as many twists and turns as a Northwoods trail, a rare insight from a massive public database and charitable support from an off-road motorcycle group have paved the way for work that may help some 20 percent of breast cancer patients with hard-to-treat tumors.

Now, funding from WARF’s Accelerator Program is helping transform the discovery by Avtar Roopra, a University of Wisconsin-Madison associate professor of neuroscience, into a predictive test and treatment kit that may serve as a model for other diseases.

“The project really encompasses the idea that we should be able to predict how a patient is going to do as soon as that person walks into the doctor’s office,” says Roopra. “From the patient’s standpoint, the benefit of the predictive assay is that it would be coupled to a second, ultimate part of the project — the development of a personalized medicine tool kit.

Roopra’s project builds on his previous research related to epilepsy and the workings of a long, powerful gene known as REST that regulates nearly 2,000 other human genes. In 2002, Roopra began exploring connections between excess REST and epileptic seizures — research that led to the development of a drug now in clinical trials to block action of the gene.

After his sister, Gurcharan Roopra- Ryatt, succumbed to an aggressive form of breast cancer, Roopra decided to turn his knowledge of gene interactions as well as his skill in computation and bioinformatics into a search for the genetic underpinnings of hard-to-treat tumors.

“I felt I should dedicate some of my effort to breast cancer research,” Roopra says. “We had no funding so we started out kind of small and we began with databases that already existed. There are literally tens of thousands of gene sets that have been archived at the National Center for Biotechnology Information (NCBI) including breast cancer and prostate tumors, all waiting to be analyzed. That’s how we discovered — utterly to our surprise — that there was a role for REST, a factor that I’d been studying for decades, in breast cancer. It had never been noticed before. It was incredibly compelling.”

In another series of unlikely coincidences, Roopra’s work caught the attention of cross-campus colleague John Newton, an HVAC specialist with the UW Biotron and an avid cross-country motorcyclist. Newton’s cycle group, the Wisconsin Dual Sport Riders, organizes two charity rides through the Northwoods each year and after learning of the work by Roopra’s team, the group selected the lab as one of its beneficiaries for the past five years.

“The effort to understand the role of REST in breast cancer has really been done on a shoestring budget and almost the entire work has been funded by this bunch of bikers raising money in northern Wisconsin,” Roopra says. “We’ve been extremely fortunate not only for the money, but because for the past three years, we’ve succeeded in getting papers published in peer-reviewed academic journals starting with PLOS Genetics. And of course in all of these publications we credit the work as being funded by the Wisconsin Dual Sport Riders.”

Now, however, the research has progressed to the point where additional money is needed to validate the reliability of the predictive tests in mouse models of cancer and begin identifying the best treatment tools to include. WARF’s Accelerator Program is providing the funding for this next step in the commercialization process.

The project revolves around identification of antibodies that detect when the REST gene is missing from breast tumors.

In these tumors, exons needed to form a normal REST gene get spliced and reconnected in alternative ways, generating a truncated protein.

“We know how REST is lost, in at least some of the cases,” Roopra said. “And when REST is lost, a number of signaling pathways get elevated. There are existing, commercially available drugs that interfere with these signaling pathways. To stop tumor growth, it appears we may not have to actually go about restoring REST, we may just have to go and shut down the signaling pathways.”

Until Roopra’s work, however, no one had made the connection between REST and the signaling pathways in these aggressive tumors. And without a test to identify the subset of breast cancer patients who have lost the REST gene in their tumors, there has been no way to study the efficacy of new drugs or target administration of the most appropriate existing medicines.

A further challenge has been the fact that some new medicines with promise to act on the RESTless signaling pathways have not made it out of clinical trials because they show overall low efficacy rates against the majority of cancer types.

“Our strong feeling is that in at least some cases, the clinical trial didn’t go so well because the drug was given to all patients and we believe only about 20 percent of patients with breast cancer have lost REST,” Roopra said. “What we’re hoping is that once it’s possible to identify patients who have lost REST and test the drugs on them, then you should start seeing efficacy.”

So, Roopra’s team is now making a major push to complete development of the antibodies that will detect the loss of REST and serve as the diagnostic portion of the tool kit. Work is underway in mouse models with completion expected in 2014.

Thanks to the long-term research on the unique genetic signature of REST and an understanding of the mechanism behind it, Roopra has identified several potential therapies likely to benefit patients who have lost REST in their tumors.

“We have a good handle on why loss of REST drives tumor progression and we’ve found points to interfere in the progression of the disease and stall tumor growth and that’s what we’re looking at right now,” Roopra says. “We know what those elevated signaling pathways are and there are already drugs that exist that inhibit those pathways. So, it’s very exciting.”

Beyond his team’s eagerness to demonstrate in more detail the initial findings of the work, Roopra also understands that subsequent phases of the project will entail greater costs to establish clinical safety and efficacy of the suite of targeted drugs. However, potential commercial partners stand to benefit not just from the immediate boost of a powerful new tool against breast cancer, but from the broader implications of Roopra’s antibody-based assay.

“This is an important test that’s going to help save lives,” Roopra says. “But the other exciting thing about all this is that we ultimately may be able to eliminate the need to biopsy the tumors and go for a blood test both for diagnosis and to monitor treatment. The three leading genes in the gene signature profile are secreted proteins and antibodies exist for those, so it should be possible to produce a noninvasive monitoring tool for these tumors.”