By Alan Fischer
TNAZ Senior Writer
Lead investigator in medicinal chemistry and pharmacology, Dr. Laurence Hurley in one portion of his labs at Bio5 Institute, part of the Medical Campus at University of Arizona in Tucson.
After more than a decade of following a novel research path, a University of Arizona scientist is poised to see his work pay off with a new class of breakthrough drug therapies aimed at the elusive ability to kill cancer cells without harming healthy cells.
Laurence H. Hurley, the Howard Schaeffer Endowed Chair in Pharmaceutical Sciences in the UA College of Pharmacy, estimated that the development of chemical agents to control the growth of or kill cancer cells may well result in treatments that could reach the public in three to four years.
"For years, cancer patients have been pumped full of poisonous cytotoxins to kill cancer cells," Hurley said. "But this conventional treatment has also resulted in the death of the surrounding healthy cells."
Typically, chemotherapy drugs target proteins responsible for a cancer's growth. But Hurley's study of DNA has found new ways to attack the disease.
"My longtime objective was to find a way to target oncogene or cancer gene expression using small drug-like molecules," he said. "Oncogenes can help turn a healthy cell into a cancerous one. So the Holy Grail in cancer research has been to target the on/off switch mechanism that controls oncogenes."
Hurley's study of DNA quadruplexes is paving the way for a new class of cancer drugs. Quadruplexes are four-stranded structures found on the single-stranded ends of chromosome telomeres, where replication of DNA in cells takes place.
"Under certain circumstances, DNA's duplex strands open up to form single-stranded regions and result in quadruplexes," Hurley said. "Our research group began to make real progress in identifying a new molecular target when we began looking at DNA as not only a static molecule that has a defined structure, but thinking about DNA as an exceedingly dynamic molecule that can form many different structures as it writhes, twists and untwists."
Hurley's research team used a number of techniques, including molecular modeling, to come up with molecules that would target these new nuclear receptors very selectively.
"Our mission is to find a way, with small drug-like molecules, to be able to target the switch mechanism that controls the oncogenes that can turn off a cancer cell, Hurley said. "We've discovered a new way to target this on/off switch that came from a fresh understanding of the nucleic acid itself, like DNA, which, under certain dynamic stresses, forms unusual globular structures that look like ‘knots.'
"What we now know is that these knot-like structures are in areas of the DNA that control the switch mechanism. And with that understanding, we have been able to design molecules that selectively target these globular structures," he said.
"We figured that, if these structures were in the ends of chromosomes of cancer cells, we could target them and preferentially kill cancer cells over normal cells," he said. "So we've worked toward designing and making molecules that interact with these ‘knot-like' structures to disrupt the events that happen at the ends of chromosomes, which are critical for cell reproduction."
Hurley's research ideas initially were met with skepticism from the research community, funding entities and scientific journals, but they now have embraced his findings.
Dr. Laurence Hurley's work in combinatorial chemistries and pharmacology is well known world-wide, as this twice-visiting delegation from Osaka University attests. Those with Hurley at his Bio5 Institute labs include Taku Yamashita, Yoshiaki Okamoto, So-Ichiro Fiulcada, Tadayulei Uno, Keisuke Tachibana and Kiyoji Hanasaki.
"In recent years, hundreds of other scientists have cited our work published in Journal of Medicinal Chemistry and Proceedings of the National Academy of Science," he said.
Hurley launched a company in 2000 with longtime collaborator Daniel Von Hoff, professor of medicine, pathology, and molecular and cellular biology at the UA and then-director of the Arizona Cancer Center. The purpose of their company was to commercialize their research and move toward offering the public new therapies to battle cancer.
"The first quadruplex-targeted drug (Quarfloxin), a first-in-class, was developed and was given to a patient in August 2005 in testing," Hurley said. "Quarfloxin is now in U.S. Food and Drug Administration Phase 2 clinical trials to prove efficacy, with earlier tests proving its safety," he added. "If testing results of Quarfloxin continue to be positive, the drug could possibly be made available to the public in the next three to four years."
"For generations of quadruplex-based therapies that will follow, the time line is obviously longer, and we're talking another seven to 10 years," he said.
Harold Kohn, Kenan Distinguished Professor, Division of Medicinal Chemistry and Natural Products, University of North Carolina-Chapel Hill, said, "The discovery of a new class of receptors for drug action is an important milestone because it provides a novel approach of treating cancer and potentially other diseases. Accordingly, this is a very significant discovery."
"Quarfloxin is a novel agent that was specifically designed to induce cancer cell death by disrupting an essential protein-rDNA quadruplex complex," said Kohn, whose research looks at the design and synthesis of new chemotherapeutic agents for the treatment of epilepsy, cancer and bacterial infections.
Like a number of cancer researchers, Hurley has lost family and friends to the disease.
"We're specifically trying to target a number of cancers, particularly pancreatic cancer," he said. "From a personal perspective, my father died in 1975 of pancreatic cancer. The last time I was with him he was in hospital at Bath University in the U.K., and I told him -- I made a pledge to him -- that I was going to try to do something about this disease.
"I actually changed my research focus considerably because of the death of my father," Hurley said. "His death really keeps me focused on what the goal is here. The goal is to get effective drugs into people that will make a difference."
Growing acceptance of his research by colleagues, publications and funding agencies means more focus on using quadruplexes to battle cancer.
"Funding is coming in and our publications are being accepted and rigorously peer-reviewed," Hurley said. "I think the quadruplex area will continue to show tremendous potential in the fight against cancer."
Editors Note: Dr. Hurley is also a member of the Arizona Cancer Center and the Bio5 Institute at UA.