May 1, 2002

RTI Wins Prestigious Grant to Seek Cancer Drugs from Mushrooms

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Research Triangle Park, NC - The American Cancer Society has awarded a three-year, $716,000 grant to RTI to seek anti-cancer pharmaceuticals from mushrooms.

Nicholas H. Oberlies, PhD, is principal investigator for the research. Dr. Oberlies works in RTI's renowned Natural Products Laboratory, in which the cancer drugs Taxol® and camptothecinTM were discovered from samples of tree bark.

The prestigious "Research Scholar Grant" will enable RTI researchers to test more than 10,000 different mushroom species to see if they contain chemicals that have potential as chemotherapy drugs.

For more than 50 years, the American Cancer Society has been identifying and funding researchers who have potential to make major contributions to cancer research.

"Dr. Oberlies is one of the brightest young scientists I have ever known," said RTI Chief Scientist Monroe E. Wall, PhD, co-discoverer of both Taxol and camptothecin. "He has the potential to become a leader in the discovery of pharmaceuticals from natural sources."

Dr. Oberlies earned his PhD in medicinal chemistry and pharmacognosy in 1997 from Purdue University. After postdoctoral study at American Cyanamid, Inc., he joined RTI's Natural Products Laboratory in 1998. He is a peer reviewer for the Journal of Natural Products, and in 2001 he cofounded the American Society of Pharmacognosy's Younger Members Committee and served as its first chairperson.

In 1997, he received three significant awards for emerging researchers. These included the Abbott Medicinal Chemistry Award for Excellence in Research from the Purdue Department of Medicinal Chemistry and Molecular Pharmacology, the Jenkins/Knevel Award for Excellence in Research from the Purdue School of Pharmacy, and the Kilmer Prize, jointly awarded by the American Society of Pharmacognosy and the American Pharmaceutical Association.

The RTI project will be supported by American Cancer Society grant number RSG-02-024-01-CDD, "Isolation of Potential Anticancer Agents from Basidiomycetes (Mushrooms)."

The American Cancer Society (ACS) is a nationwide, community- based voluntary health organization. Headquartered in Atlanta, Georgia, the ACS has state divisions and more than 3,400 local offices.

RTI is an independent, nonprofit research organization dedicated to conducting research that improves the human condition. With a staff of more than 1,900 people, RTI turns knowledge into practice in the fields of health and medicine, environmental protection, technology commercialization, decision support systems, and education and training.


ABSTRACT

Name of Principal Investigator: Nicholas H. Oberlies Title of Project: "Isolation of Antitumor Agents from Basidiomycetes (Mushrooms)"

The long-term goals of this proposal are to identify and develop promising compounds from extracts of basidiomycetes (mushrooms) for the treatment of cancer. To achieve these goals, the specific aims are to:

  • Screen a collection of >10,000 basidiomycete species for cytotoxicity against a three-cell panel of 9KB (human oral epidermoid carcinoma), PC-3 (human prostate adenocarcinoma) and T-47D (human ductal mammary carcinoma)
  • Prioritize the confirmed actives based upon activity in the three-cell panel, supply available, previous work in the literature, HPLC analysis and LC/MS dereplication
  • Purify the cytotoxic constituents from the crude extract using bioactivity-directed fractionation procedures
  • Characterize the pure, cytotoxic compounds using advanced spectroscopic techniques such as 1 and 2D NMR, mass spectrometry, x-ray crystallography, etc.
  • Evaluate pure compounds in several different antitumor bioassays, both in house at RTI and in the 60-cell line antitumor assay through a long-standing collaboration with the National Cancer Institute (NCI) (see appendix for letter of support from the NCI)

Although significant progress has been made over the last thirty years during the "War on Cancer," the disease kills thousands of people in the U.S.A. every day. One area of research, the discovery of novel anticancer agents from natural sources, has resulted in the development of many new chemotherapeutic agents. Two of these, Taxol, and camptothecin, were discovered at Research Triangle Institute (RTI) initially as the cytotoxic principles of the plants Taxus brevifolia and Camptotheca acuminata, respectively. To do so, thousands of plants were screened to direct the research toward several promising leads, which led to the eventual discovery of these two life-saving compounds.

In an analogous manner, this proposal will examine thousands of fungal extracts for cytotoxicity. This group of fungi, the basidiomycetes (mushrooms), has been selected because they largely have been overlooked in anticancer screening protocols.

Using modern techniques, the promising fungal leads identified will be fractionated on a larger scale, and the pure cytotoxic compounds will be characterized. Bioassays will be used to evaluate the anticancer potential of the pure compounds.

Preliminary screening of 672 samples has identified 26 promising leads. By fractionating one of these leads, a pure, cytotoxic compound was isolated. Since the initial submission of this application, two of the aforementioned active leads have been investigated further for their ability to kill cancer cells. In doing so, we have found promising cytotoxicity against various cancer cell types. Also, we have added a dereplication step to our prioritization protocol. Doing so has focused our efforts on samples where that are most likely to yield novel anticancer compounds.

Taxol, a word coined by Monroe E. Wall of RTI, is a registered trademark of the Bristol-Myers Squibb Company. Camptothecin is a trademark of RTI.