From left: collaborators Serguei Kozlov, Ph.D.; Udo Rudloff, M.D., Ph.D.; and Tomas Vilimas, Ph.D. (Left photo by Richard Frederickson, staff photographer. Center photo courtesy of Rudloff. Right photo courtesy of Vilimas.)
Serguei Kozlov, Ph.D., doesn’t recall if it was he who first contacted clinician Udo Rudloff, M.D., Ph.D., or Rudloff who contacted him. He just knows that their resulting two-year collaboration, which recently moved a first-in-class drug for metastatic cancer toward clinical trials, is one of the best he’s ever had.
A few years ago, Frederick National Laboratory’s Center for Advanced Preclinical Research (CAPR), which includes Kozlov and his lab, underwent a structural change and began seeking new partners. Meanwhile, Rudloff and his team, part of the Rare Tumor Initiative of the Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, joined a collaborative study of metarrestin, an experimental cancer drug with the potential to eliminate metastases—cancer cells that have spread from an original tumor to new sites in a patient’s body.
Kozlov and his fellow preclinical researchers at CAPR wanted to support a clinician’s research by using CAPR’s mouse models of human cancer. Rudloff and his collaborators, Juan Marugan, Ph.D., at the National Center for Advancing Translational Sciences (NCATS) and Sui Huang, M.D., Ph.D., at the Northwestern University Feinberg School of Medicine, needed skilled preclinical researchers to study metarrestin before it could be tested in humans.
“And then something just clicked,” Kozlov said. “So, we sat together, and all of a sudden, we … realized we could move this project very efficiently.”
They were right. Last year, the four collaborators and their teams demonstrated that metarrestin effectively disrupts metastasis in three types of preclinical cancer models, including an often-lethal form of pancreatic cancer. Mice treated with the drug showed reduced metastatic cancer burden and subsequently had a much longer life span than they otherwise would have.
“It literally kind of cured [them],” Rudloff said. “After six months, the cancer still did not come back.”
The results were preliminary, but in light of current estimates that 80–90 percent of cancer deaths are due to metastasis and related complications, they suggest that metarrestin may be a promising and much-needed drug for increasing patients’ life expectancies and quality of life.
In a follow-up study led by CAPR and Rudloff’s lab, metarrestin passed another challenge in drug development. The researchers showed that it was safe and nontoxic in a mouse model of aggressive pancreatic cancer that closely resembled cancer in humans. Mice treated with metarrestin, even those that received high doses, suffered no side effects and were similar to healthy, tumor-free mice that didn’t receive the drug. In addition, the levels of the drug measured in the tumor easily surpassed those required for it to be effective.
“That was a really detailed, careful study of metarrestin’s organ distribution and toxicity that showed that it’s likely to be suitable for human applications without toxicity at efficacious doses,” said Tomas Vilimas, Ph.D., the study’s lead author and former CAPR scientist. (He is now part of the Molecular Characterization Laboratory at the Frederick National Laboratory.)
“It was very exciting that it passed this hurdle of toxicity, because a lot of drugs fail at this step,” he added.
“When People Work Together…”
Kozlov says the successful research was due in part to constant communication between the collaborators. During the toxicity study, CAPR and Rudloff’s lab shared an open-door policy, data was uploaded to the cloud so the partners could easily analyze and discuss it, and Rudloff often visited CAPR during his frequent trips to Frederick from his Bethesda laboratory.
“I used to say that I probably talk to him more than I talk to my spouse!” Kozlov said, adding that he and Rudloff exchanged hundreds of emails while working together. “When there’s a good idea, it’s got to be discussed right now.”
Rudloff also attributes their success to the dedication and diverse expertise of every collaborator, such as NCATS’ original discovery and optimization of metarrestin or CAPR’s extensive capabilities with preclinical mouse models.
CAPR ran the mouse studies as if they were trials in human patients, using stringent protocols, methods, and ethical guidelines. On a few occasions during the toxicity study, Vilimas even returned to the lab in the middle of the night so he could collect data and monitor the mice.
“The rodent, the mouse animal studies are just state of the art,” Rudloff said. “The ability to conduct pharmacokinetic studies in a transgenic animal model which resembles the human cancer so closely is a huge advantage where drug delivery to tumors is a major reason for current therapies not working.”
Both Kozlov and Rudloff say that their respective labs also learned from each other and adjusted their usual practices because of the collaboration, improving the way they work.
The duo plans to continue their partnership to research metarrestin and hopes to examine the extent to which metarrestin’s target is involved in the drug’s organ distribution and toxicity.
With the support of NCATS’ Bridging Interventional Development Gaps program, metarrestin has completed the studies required to file an Investigational New Drug application with the U.S. Food and Drug Administration. Rudloff is currently obtaining the necessary approvals for a clinical trial in humans, which he hopes to launch this fall.
Kozlov and his group will perform co-clinical trials and attempt to optimize their mouse models to provide more information about metarrestin’s antitumor potency. There is also talk of a possible post-clinical trial in which the collaborators would compare metarrestin’s in-human and in-mouse performance to find new ways to improve the drug.
“What I like about this project is, I think we have demonstrated pretty clearly and very convincingly that it does ‘take a village’ … to bring a compound to the point when it is actually a good candidate for clinical translation,” Kozlov said.
Rudloff agreed, adding, “What it all comes down to is, … when people work together, you can really do amazing things.”
