If you set out to fmd a cancer drug hidden somewhere within the natural world, where would you begin? In his quest for untapped diversity that could deliver new bioactive compounds, A. Douglas Kinghorn, PhD, professor of natural products chemistry and pharmacognosy at Ohio State University in Columbus, Ohio, has ventured into tropical rainforests from the Dominican Republic to Indonesia and beyond.

By most accounts, Dr. Kinghorn has made good use of globe-spanning explorations, with a $7 million, 5-year “Discovery of Anticancer Agents of Diverse Natural Origin” program project grant from the National Cancer Institute (NCD his latest vote of confidence. Colleagues say that Dr. Kinghorn has fared better than most in securing major funding in the near absence of investment by major pharmaceutical companies, navigating the cultural and political obstacles of collecting from many foreign countries, and figuring out how to source enough material to pursue preclinical studies of some promising pharmaceutical candidates.

None of these successes ensures a rare plant from Vietnam or Madagascar will deliver the next Taxol to cancer patients, but with a range of natural products now in clinical trials, the candidates emerging from academic laboratories may help entice big pharmaceutical firms back into an arena that critics say they have all but abandoned over the past 15 years.

“It's effectively only academics and the government actually doing the discovery work these days,” says David Newman, DPhil, chief of the Natural Products Branch at NCI in Frederick, Maryland. Some smaller biotech companies have formed partnerships with academic groups, but William Fenical, PhD, director of the Center for Marine Biotechnology and Biomedicine at Scripps Institution of Oceanography in La Jolla, California, says the burden has rested largely on the shoulders of scientists scrambling for government grants. “When you consider the difference in investment and delivery of product per dollar, the academic researchers are doing far better than industry,” he says.

A Challenging and Rewarding Quest

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  2. A Challenging and Rewarding Quest

Dr. Kinghorn is frequently cited as a good case in point. For his NCI-funded project that began in 2007, he and his collaborators have sought a wide diversity of organisms by collecting tropical plants from 3 locations in Vietnam and obtaining aquatic cyanobacteria from throughout the United States, including the Chicago, Illinois, region. A consortium partner, Mycosynthetix (Hillsborough, NC), has provided access to another 55,000 fungal isolates.

To date, Dr. Kinghorn's lab has isolated several hundred natural product compounds with inhibitory activity against the growth of cancer cells. “But relatively few of these have tended to shrink tumors in relevant mouse models,” he says. One that has, a compound known as silvestrol, has shown early promise as a possible treatment for chronic lymphocytic leukemia.The compound, which Dr. Kinghorn and collaborators isolated from the fruits and twigs of the Aglaia foveolata plant in Indonesia, is being shepherded through the preclinical trial pipeline by the NCI. Dr. Kinghorn says the immediate goal is to obtain another 25 grams for preclinical toxicology studies.

This is no trivial task, considering that some researchers have been thwarted by amassing even milligrams of a prospective drug to conduct preliminary studies. For plants, Dr. Kinghorn says an active compound may be present at a yield of only 0.1% by weight of the dried organism, and often less. “When dealing with a rare plant, it may be possible to cultivate this in its country of origin for drug development purposes,” he says. In the case of silvestrol, his team is now working with the government of Sarawak, Malaysia, to obtain sufficient amounts of a related plant that also produces silvestrol to complete the next preclinical step.

The alternative, synthesizing the compound in the laboratory can cost many hundreds of thousands of dollars—a considerable gamble in the absence of compelling data. Beyond skittishness over the upfront financial risks, Dr. Newman says the availability of high- throughput screens and the allure of blockbuster lifestyle drugs have combined to create a “perfect storm” pushing the pharmaceutical industry away from natural products. Instead, the industry has embraced theoretically faster drug discovery strategies such as combinatorial chemistry.

But numbers do not lie. Although combinatorial chemistry has yielded 1 commercial anticancer compound from scratch (sorafenib), Dr. Newman has calculated that more than 100 have come from natural products or their derivatives or mimics—an estimated 65% of all anticancer small molecules ever approved.

Through a preclinical drug development program, the NCI recently supported efforts to recollect a plant in Madagascar from which Dr. Kinghorn's lab isolated pervilleine A, a compound that inhibits multidrug resistance in an in vivo mouse model. Meanwhile, the fast- evolving tools of genomic sequencing and molecular biology have helped to uncover previously hidden metabolites in collected organisms that can likewise be tested for their potential.

Despite the lingering financial, political, and logistical barriers, Dr. Newman sees such endeavors as forming a major pipeline for future therapies. “Yes,” he says, “natural products as an intellectual source of thug leads is still alive and well.”