Natural Products Laboratory: Discoveries and Awards
Discoveries
Dr. Mansukh Wani and the late Dr. Monroe Wall discovered two of the most important compounds in cancer chemotherapy, Taxol® and camptothecinTM, with funding from the National Cancer Institute (NCI). By isolating and elucidating the structure of these novel, bioactive natural products, they have saved hundreds of thousands of lives, unearthed new mechanisms of action for inhibiting cancer cell growth, and established new principles for discovering other bioactive compounds from natural sources. The sales of Taxol and camptothecin analogs in the U.S. alone account for more than one-third of the market for antineoplastic agents.
Camptothecin
Drs. Wall and Wani and their colleagues reported the discovery of a compound they termed camptothecin from the Chinese "happy tree", Camptotheca acuminata, in 1966. The unique mode of action for this potent cytotoxic compound was found to be the inhibition of an enzyme known as DNA topoisomerase I. Camptothecin traps this enzyme, inhibiting DNA replication and killing the cancer cells.
First-generation analogs of camptothecin include GlaxoSmithKline's Hycamtin (topotecan) and Pfizer's Camptosar (irinotecan or CPT-11), approved by the FDA for the treatment of small cell lung, ovarian, and colon cancers. More than nine camptothecin analogs are in clinical trials for leukemia, pancreatic, lung, and ovarian cancers.
See the timeline showing how camptothecin was discovered and developed.
Taxol
In 1971, Drs. Wall and Wani reported the structure of Taxol found in the Pacific yew tree, Taxus brevifolia. The unique mode of action for this compound was found to be the stabilization of microtubule assembly, an important step in cell division. This mode of action, discovered by Dr. Susan Band Horwitz at the Albert Einstein College of Medicine, is unlike any other anti-cancer compound. The first total synthesis of the Taxol molecule was reported by Florida State University researcher Robert Holton.
Bristol-Myers Squibb received approval in 1992 for Taxol's treatment of refractory ovarian cancer, and subsequently it was approved for the treatment of metastatic breast and lung cancers and Kaposi's sarcoma. Currently, Aventis' Taxotere has FDA approval for locally advanced or metastatic breast cancer, non-small-cell lung cancer, and hormone-refractory prostate cancer.
There are more than 17 Taxol analogs in clinical trials for breast, prostate, brain, skin, pancreatic, colorectal, and lung cancers. In addition, Taxol-coated stents are currently used in angioplasty to prevent restenosis, the re-blockage of the surgically cleared blood vessel that occurs in 10-30% of procedures with older bare-metal stents. Taxol-coated stents dramatically reduce the need for repeat angioplasty procedures.
See the timeline showing how Taxol was discovered and developed.
Breakthroughs in Methodology
A significant aspect of the discoveries of Taxol and camptothecin by Drs. Wall and Wani was their innovative application of novel anticancer bioassays. To isolate and characterize both compounds, they used a then-novel method known as bioactivity-directed fractionation. In this process, a promising extract is subdivided into like compounds called "fractions." The fractions are tested for disease-fighting activity. The process is repeated on each active fraction in an iterative manner. With retesting and repetition of the fractionation, the active compound is isolated.
Drs. Wani and Wall also pioneered the use of in vitro cytotoxicity (cancer-killing ability in the laboratory setting) as a predictor of in vivo efficacy (cancer-killing ability in a living organism). By using these in vitro tests to predict whether compounds would have anticancer activity in humans, they were able to focus and accelerate their research toward new treatments. Today, these techniques are used routinely as best practices in natural products laboratories around the world to discover bioactive compounds.
Awards
Charles F. Kettering Prize
Drs. Wall and Wani received the 2000 Charles F. Kettering Prize for outstanding contributions to the diagnosis and treatment of cancer. They were cited for the discovery of Taxol® and camptothecinTM, both of which have unprecedented mechanisms of action against cancer.* The Kettering Prize is among the most prestigious in the field of medicine.
American Chemical Society National Historic Chemical Landmark
The American Chemical Society honored RTI's Natural Products Laboratory with a National Historic Chemical Landmark commemorating the discovery of Taxol and camptothecin by Dr. Mansukh Wani and the late Dr. Monroe Wall. These compounds, both derived from plants through seminal research at RTI in the 1960s and 1970s, are two of today's frontline pharmaceuticals in the fight against cancer.
President's Teaching Scholar, University of Colorado
Dr. David Kroll was elected to the academy of President's Teaching Scholars of the University of Colorado in 2000. This lifetime honor recognizes the past contributions and ongoing activities of tenured, research professors who have also demonstrated distinction in the educational arena.
Triangle Business Journal "40 Under 40" Award
Dr. Nicholas Oberlies was named one of the top 40 business leaders under 40 years of age by the Triangle Business Journal. The award acknowledges Dr. Oberlies's ability to balance his family and community life with his professional activities at the Natural Products Laboratory.
Indiana University Distinguished Alumni Award
Dr. Mansukh C. Wani received the 2003 Distinguished Alumni Award from the Indiana University College of Arts and Sciences. Wani, who earned his Ph.D. in chemistry from the university in 1962, was praised for his "significant contributions to the world" and his "commitment to science and research."
Historical Marker at Gifford Pinchot National Forest
A historical marker was unveiled in the Gifford Pinchot National Forest near Packwood, Wash., in 2002 to commemorate the collection of the original sample of Pacific yew (Taxus brevifolia), which subsequently led to the discovery of the anticancer compound Taxol by Dr. Mansukh Wani and the late Dr. Monroe Wall. The dedication was made by the USDA Forest Service, the National Cancer Institute, and the American Society of Pharmacognosy on the 40th anniversary of the collection.
National Cancer Institute Awards of Recognition
Drs. Monroe Wall and Mansukh Wani received 1996 National Cancer Institute (NCI) Awards of Recognition for their discovery and development of the cancer drugs Taxol and camptothecin. NCI officials presented the awards in June of 1996 at "The Monroe Wall Symposium," a natural products chemistry conference held at Rutgers University.
Bruce F. Cain Memorial Award
Drs. Wall and Wani received the AACR-Bruce F. Cain Memorial Award in 1994 for outstanding preclinical research in the fields of medicinal chemistry, biochemistry, or tumor biology that has implications for the improved care of cancer patients.
Note: Taxol (a word coined by RTI's Monroe E. Wall) is a registered trademark of Bristol-Myers Squibb Co. Camptothecin is a trademark of RTI.
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