Selected Success Stories from the
Biochemistry & Pharmacology Portfolio

Research Highlights

1. R44 CA79228

Leonard Katz, Principal Investigator
Kosan Biosciences, Inc.
Heterologous Production of Epothilone

Epothilone D, a complex polyketide that inhibits the depolymerization of microtubles, is currently in Phase I clinical trial. Katz and coworkers identified, cloned and sequenced the genes responsible for the synthesis of Epothilone D. Using vectors and methods developed at Kosan, they inserted the gene cluster from S. cellulosum into the chromosome of Myxococcus xanthus, a related, but faster growing bacterium. Next, they developed fermentation and product recovery protocols for the production and high-level purification of sufficient product to support clinical trials at a reasonable cost. This work represents the first example of heterologous production of a small molecule to reach the clinic. It also represents the largest segment of DNA 956KB) that has been used successfully for heterologous expression.

Tang, L. et all Science, 287, 640-642 (2000); Julien, B. eta all Gene 249, 153-160 (2000); Arsianian, R.L. et al J. Nat. Prod. 65. 570-572 (2002); Lau, J. et al Biotech & Bioeng. 78, 280-288 (2002).

2. R01 CA78577

Jessie Au, Principal Investigator
Ohio State University

Dr. Au has found that acidic and basic fibroblast growth factors induce resistance to multiple anticancer drugs with different mechanisms of action. Based on these results, a clinical trial has been initiated which includes suramin, an inhibitor of multiple growth factors, as a way to sensitize tumors to chemotherapy.

SaeHeum Song, M. Guillaume Wientjes, Yuebow Gan, and Jessie L.-S. Au.

Fibroblast growth factors: An epigenetic mechanism of broad spectrum resistance to anticancer drugs
PNAS 97:8658-8663,2000

3. R01 CA35635

Jonathan B. Chaires,
University of Mississippi Medical Center

Allosteric, chiral — selective drug binding to DNA

A research team has achieved an advance in the search for compounds capable of recognizing and modifying DNA on the basis of its shape rather than its sequence. The team demonstrated that WP900, an enantiomer of daunorubicin, binds to left-handed (2-DNA) form of a synthetic DNA polynucleotide. When used in conjunction with daunorubicin, which binds to a right-handed DNA (B-DNA), the DNA polynucleotide can be converted back and forth between its left-and right-handed forms. For more information, see the following:

Xiaogang Qu, John O. Trent, Izabela Fokt, Waldemar Priebe, and Jonathon B. Chaires

From the Cover: Allosteric, chiral-selective drug binding to DNA
PANS 97: 12032-12037; 2000

Michael Warring
Facilitating structural transitions in DNA
PANS 97: 11685-11687, 2000.

4. DEKK-TEK

DEKK-TEK, with Dr. Lee Roy Morgan as Principal Investigator, received several SBIR awards administered by PTGB staff. Through this support three agents are in clinical trial. A-007, a dinitrophenylhydrazone, was originally developed as a potential cervical cancer treatment agent. Later studies demonstrated its utility for cervical dysplasia treatment for which the agent is currently in Phase II/III trials. Trials for cervical cancer are on hold at this time. An isophosphoramide mustard, IPM/ZIO-201, has been developed with SBIR support and now is in Phase II/III trials, in combination with adriamycin, for treatment of soft tissue sarcomas. A novel penclomidine analog, DM-CHOC-PEN, has been reviewed by the FDA and will soon be ready for Phase I trials at MD Anderson and Tulane University in adult and pediatric patients with inoperable brain tumors. Three additional agents are at various stages of development and should be considered for clinical trials in the near future.

5. AntiCancer, Inc.

AntiCancer Inc., through SBIR grants, developed animal models utilizing fluorescent proteins. Many of the grants were supported by PTGB. Details on this successful research can be found at: http://sbir.cancer.gov/success/stories/AntiCancer/AntiCancer_Success_Story.asp

6. PEMETREXED

PTGB has throughout the years supported grants to several investigators related to folate analog biochemistry, pharmacology and cancer therapy. These studies have led to a detailed understanding of the mechanism of action of the agents. From the funded research of several investigators PEMETREXED was discovered, thoroughly evaluated, and recently approved by the FDA for front line treatment of mesothelioma and non-small cell lung cancer. PEMETREXED is the first anti-fol to gain FDA approval for cancer treatment since methotrexate.

The PEMETREXED precursor, lometrexol, was synthesized by E.C. Taylor at Princeton and Chuan Shih at Eli Lilly. Lometrexol has significant anti-tumor activity as an anti-metabolite. Importantly, from PTGB-supported research by G. Peter Beardsley and Richard Moran it was learned that lometroxol biochemistry was novel in that it inhibited not only dihyrofolate reductase, but also thymidylate synthase and glycinamide ribonucleotide transferase. Lometrexol had the disadvantage of being a mixture of two diasteromers, a feature unacceptable to the FDA. Shih and colleagues, then synthesized PEMETREXED with only one stereoisomer. Importantly, is possessed powerful antiproliferative activity and maintained the novel biochemical features.