KPC34: The Leukemia Therapeutic That Almost Never Was

Though he speaks about it now with a smile, there is a faint echo of old frustration in Greg Kucera’s voice. He’s talking about the project that has become a life mission of sorts.

“I knew the drug was good,” he says, “I just couldn’t prove it.”

The drug Kucera refers to, KPC34, is a therapeutic he and his team developed to treat acute leukemia. A therapeutic that almost never existed.

In 1990, Greg Kucera, PhD, joined Wake Forest School of Medicine to research lipid metabolism in cancer. Some of his research became a family affair as he collaborated with his father, Louis Kucera, PhD, a virologist also on the faculty at Wake Forest. Together father and son founded a startup company, Kucera Pharmaceuticals, to develop antiviral and anticancer drugs.

Under the umbrella of Kucera Pharmaceuticals, Greg Kucera began conjugating lipid molecules to therapeutics, hoping to change how cancer cells metabolized the drugs, thereby increasing their effectiveness. He and his team synthesized several compounds, and one in particular showed potential. When tested in vitro, the KPC34 compound performed as well as the standard of care therapeutics used to treat acute leukemia. Kucera found himself on the brink of a major discovery.

Then September 11th happened.

Financial markets got shaky, investors got cold feet and funding for startups dried up nationally. Kucera Pharmaceuticals limped along on grants from the National Institutes of Health and the North Carolina Biotechnology Center. But their antiviral medications did not pan out, and industry partners showed no interest in further developing their anticancer compounds. Kucera and his father could not keep the startup going, and in 2007 Kucera Pharmaceuticals closed its doors.

With it, research on KPC34 halted.

“Every once in a while we would pull the compound out and do something with it,” Kucera says, “but that was the extent of it.” He was convinced of KPC34’s potential, but he lacked the vital element that would prove it.

KPC34 might have remained on the shelf indefinitely, if not for the arrival of a new face at Wake Forest: Timothy Pardee.

Like Kucera, Pardee, MD, PhD, researches acute leukemia therapeutics. He started testing therapeutics during his postdoctoral fellowship at the Scott Lowe Laboratory in Cold Spring Harbor, NY, where he developed expertise in models of acute myeloid and lymphoblastic leukemia.

Unlike Kucera, Pardee specializes in both the preclinical and clinical aspects of therapeutic development.

“Because I treat leukemia clinically,” Pardee says, “my research focuses on the translational steps of moving therapeutics from preclinical testing to a place where they could potentially help my patients.”

Body-Kucera&Pardee

When he joined the faculty at Wake Forest in 2009, Pardee brought his expertise in and passion for leukemia research. He also unknowingly brought the missing piece of the KPC34 puzzle: a novel and accurate mouse model of leukemia.

Something as simple as proximity ended up being the twist of fate that led Kucera to the leukemia model Pardee had developed. The two scientists worked in the same section of hematology and oncology at Wake Forest, and they occupied offices around the corner from each other.

In 2011, nearly six years after Kucera first discovered KPC34, the biochemist tested his novel therapeutic in Pardee’s mouse model of leukemia.

The results astounded the researchers. The compound, which previously tested only as well as current therapies in vitro, suddenly showed distinct advantages over standard-of-care treatments.

The lipid molecule attached to KCP34 allowed the drug to bypass the mutated resistance mechanisms of leukemia cells, allowing the drug to cross the blood-brain barrier and increasing its effectiveness.

Cancer cells tend to build up resistance to therapeutics, causing subsequent treatments to decrease in effectiveness. KPC34 behaved differently. The leukemia did not become resistant to the novel compound, and the preclinical models continued to respond well to repeated treatments with the therapeutic.

KPC34 also reversed many of the side effects caused by the disease in mouse models. As leukemia progresses, quality of life decreases as patients lose function and mobility. In preclinical tests of KPC34, the new compound actually reversed these deficiencies and improved quality of life.

In an unexpected twist, KPC34 proved most effective when taken orally, making it different from current therapies, which are administered by injection and require patients to come to the hospital for treatments. Kucera and Pardee’s discovery meant KPC34 could potentially be given in pill form, decreasing the inconvenience and discomfort of leukemia treatments.

Kucera and Pardee believe this novel drug may extend the lifespans of people suffering from leukemia, hopefully allowing them to spend additional time with their families with decreased pain and increased function.

“The outcomes for adults with acute leukemia are horrendously poor, and current treatment options are not great,” Pardee says. “To have a treatment that patients could take in a pill form that can improve quality of life would be a huge step forward.”

Though the journey has been filled with setbacks and frustrations, Kucera and Pardee’s belief in the therapeutic is finally coming to fruition. After more than a decade of development, KPC34 is moving closer to being tested in clinical trials.

Kucera and Pardee are searching for an industry partner to collaborate with them for the last stages of drug development. They hope that the therapeutic with an unlikely existence will find the final collaboration that propels it to point where it impacts the lives of the patients who need it most.

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