Susan Band Horwitz, Ph.D.
Albert Einstein College of Medicine
Bronx, New York

"Searching for natural products that are analogues of Taxol that circumvent the problem of tumor multi-drug resistance"

Background:

In the early 1970s, from the bark of Western yew, Taxus brevifolia, Drs. Wall and Wani identified a compound with a unique chemical structure that exhibited antitumor activity.

However, the study of this compound, paclitaxel, was very limited at that time because of the lack of efficient extraction and production techniques. In 1979, a pharmacologist at the Albert Einstein College of Medicine, Dr. Susan Band Horwitz, identified paclitaxel's mechanism of action against cellular division.  After a decade of intensive study, this compound has led to the development of an anticancer drug currently serving as the first line of treatment for breast, ovary, and non-small cell lung cancer - Taxol.

Taxol manipulates the assembly and disassembly of microtubules, which are essential components of a diverse range of cellular functions including cellular division, cell mobility, maintenance of cell shape, and intracellular trafficking of macromolecules. Despite the significant inhibitory effect of initial Taxol treatments, continued therapy is usually hindered by the resistance cancer cells often develop toward this drug.

Fellow and Research:

As current President of the American Association for Cancer Research (AACR), Dr. Horwitz is also a Falkenstein Professor of Cancer research and co-chair of the Department of Molecular Pharmacology at the Albert Einstein College of Medicine, Bronx, New York. Her recent focus has been trying to identify new agents that can circumvent the problem of Taxol drug resistance.

Two natural compounds, epothilone and discodermolide, were isolated from bacteria found in soil samples of southern Africa and a type of Caribbean Sea sponge.  There is evidence indicating that these two molecules, although with similar mechanisms of action to Taxol, still remain active in Taxol resistant cancer cells.  Dr. Horwitz's research further demonstrated that by combining Taxol and discodermolide, these two drugs acted synergistically and killed more cancer cells than Taxol or discodermolide alone. Dr. Horwitz's group is currently participating in a clinical trial with a new epothilone analog and observing how Taxol resistant cells modify their biochemical properties in order to live in the presence of the drug.

Impact on Cancer Prevention, Treatment, or Cure:

The introduction of Taxol in the 1990s was an important advance in the treatment of breast and ovarian cancer.  However, some tumors are inherently resistant to Taxol and others develop resistance to this drug during the course of chemotherapy. Finding compounds to overcome such resistance would greatly benefit patients who have malignancies that did not respond to Taxol, or that originally responded yet decreased their susceptibility to this drug.