The tearful father stood in front of André Bachmann’s poster, seeking hope of a better treatment for the devastating cancer afflicting his child. It wasn’t a typical scientific conference query, but Bachmann, an associate researcher in the University of Hawaiʻi’s Cancer Research Center of Hawaiʻi, suggested they talk over coffee.
The compound described in his poster was a long way from human clinical trials, Bachmann told the father. However, another drug under study, already approved for other uses, might be available sooner.
Ultimately, it was the parent who put Bachmann, a PhD molecular biologist, in touch with University of Vermont-based pediatric oncologist Giselle Sholler, who became an essential clinical partner in moving laboratory “bench” research into an actual drug trial that enrolled its first patient in February 2010.
Bachmann relates the story to explain why he does cancer research. But it also illustrates the dual approaches he takes as part of the UH cancer center’s Natural Products and Cancer Biology Program—finding new compounds in nature and finding new uses for current or retired drugs.
Bachmann works on neuroblastoma, a cancer of nerve tissue that affects about 650 children a year in the United States. While long-term prognosis can be good, relapse is usually a death sentence.
He focuses on proteasome inhibitors. Like a tiny paper shredder, the proteasome breaks proteins down into peptides, which can be recycled. Without this turnover, cancer cells couldn’t grow, so he is always on the lookout for potential inhibitors—molecules that can jam the shredder’s teeth.
On a trip to his native Switzerland, Bachmann visited University of Zurich plant biologist Robert Dudler, who showed him a molecule that he had isolated from a bacterium that infects bean plants. The structure was similar to other molecule groups that affect cancer cells, so Bachmann brought a few grains back to his Honolulu lab, where it shut down neuroblastoma and ovarian cancer cells.
Chemists at the Max Planck Institute in Germany were able to synthesize the molecule, called syringolin A, in sufficient quantities to investigate further. Not only was syringolin A a proteasome inhibitor, but it represented a new, seventh class of inhibitors, the international group reported in the April 10, 2008 issue of Nature.
“Now, with the tools to make the molecule, we can make analogs and test new variants to find one that is more potent,” Bachman says. He filed a patent to ensure that pharmaceutical companies would have incentive to invest in the research and move the project beyond the pre-clinical research stage.
“Sometimes we find in nature molecules we could not imagine,“ he muses. Other times, answers may sit overlooked on pharmaceutical shelves.
Such was the case with difloromethylornithine or DFMO, a drug used to treat African sleeping sickness disease. It was already FDA approved and shown to be safe with low side effects, and it had shown some promise in treatment of prostate cancer.
Bachmann began testing the drug’s affect on neuroblastoma cells in vitro under a grant from the Hawaiʻi Community Foundation in 2002. The results were encouraging enough to secure National Cancer Institute funding for continued work, and the drug was shown to cure neuroblastoma cancers in mice by inhibiting an enzyme implicated in aggressive tumor development.
The work is described in a cover article scheduled for the May 2010 issue of International Journal of Cancer.
Meanwhile, Vermont’s Sholler helped write the clinical trial protocol for the human studies, in which DFMO will be provided in combination with a second drug that is used successfully in milder cases of the disease.
Analysis of bone marrow metastases from all the patients will be done at the Cancer Research Center of Hawaiʻi. The first patient was enrolled in Vermont; eventually 10 hospitals across the country, including Kapiʻolani Medical Center in Honolulu, are expected to participate in the trial.
Bachmann’s involvement with the national consortium is important in bringing the drug trial to Honolulu, which usually sees just a handful of new neuroblastoma cases a year.
“It’s satisfying to advance something,” Bachmann says. “That’s why we look at existing drugs—it saves everybody money and time” in developing new treatments, he adds. “That is what’s important to parents.”