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 tree, 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. It has been used in over a million patients worldwide.

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 movement of macromolecules inside of cells. Despite the significant inhibitory effect of initial Taxol treatments, continued therapy is usually hindered by the resistance which cancer cells develop.

NFCR Fellow and Research

A former President of the American Association for Cancer Research (AACR), Dr. Horwitz is the 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 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. These drugs may be useful in treating tumors that are resistant to Taxol.

Dr. Horwitz is also interested in identifying novel targeted anti-cancer drugs that can be used in combination with Taxol to generate synergistic cancer-killing effects. Drugs used in such "rational combination" potentiate each other's anti-tumor effects, thereby requiring lower concentration of each drug and resulting in decreased toxicities and side effects. Targeted therapeutics that inhibit cell signaling through MEK or mTOR pathways in a cancer cell are potential candidates that may be used in combination with Taxol.

Determining a patient's sensitivity to Taxol

Not every patient treated with Taxol responds well to the drug. Dr. Horwitz reasons that this may be due to the ability of cancer cells to alter the type of tubulin proteins they express so that Taxol cannot bind to them and rendering Taxol "off the target". To focus on this very important issue, she recently developed new techniques that enable her team to isolate and identify the different types of tubulin expressed in lung and breast cancer cells as compared to normal cells. Importantly, her team will be able to learn if different types of tubulin proteins have varying sensitivity to Taxol. Dr. Horwitz's research is of high impact as it may be possible, by analyzing the type of tubulin expressed in a patient's cancer cells, to determine if they will respond effectively to Taxol even before the onset of treatment.

Impact on Cancer Prevention, Treatment, or Cure

The introduction of Taxol in the 1990s was an important advance in the treatment of breast, ovarian, and lung 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. A screening program may be developed to determine if a patient's tumor will respond effectively to Taxol before the onset of their treatment, allowing doctors to choose the most effective anti-cancer therapies for their patients.