Susan B. Horwitz, PhD

2007-2008 BCRF Project:
Taxol has an important role in the treatment of breast cancer. However, many patients have tumors that are intrinsically resistant to the drug or acquire resistance during treatment. Although many studies have been done in the laboratory to understand and reverse drug resistance, no drugs have been developed that have proven useful in patients.

Dr. Horwitz's objective is to test whether genes cause cells to become Taxol resistant. This is not a new idea, but other researchers have focused on whether genes cause resistance by acquiring mutations. Dr. Horwitz's approach is different; her team will explore whether genes switch off (or on) inappropriately in breast cancer cells. It is known that cancer is associated with major abnormalities in the way genes get switched off and on, through what are called epigenetic mechanisms.

Dr. Horwitz's group is uniquely able to look for epigenetic changes in breast cancer cells because of novel technology developed at Albert Einstein College of Medicine, allowing them to pinpoint the genes that could be responsible for drug resistance. These epigenetic changes are worth looking for because, unlike DNA mutations, they can be reversed by drugs that are already being tested in other diseases. The work is designed to tell us whether the same drugs should be used in drug-resistant tumors, with the goal of reconstituting drug sensitivity. Furthermore, the results of the proposed studies could direct the development of new drugs that reverse drug resistance and enhance Taxol sensitivity in breast cancer.

Mid-Year Progress Report:
Dr. Horwitz reports that during the past four months, Taxol–resistant cells derived from four different breast cancer cell lines have been isolated. These cell lines are now being analyzed for epigenetic changes that could be responsible for the inappropriate activity of genes, thereby resulting in drug resistance.

Bio:
Dr. Susan Band Horwitz is a Distinguished University Professor at the Albert Einstein College of Medicine and Associate Director for Therapeutics at the Albert Einstein Cancer Center. She grew up in Boston and after graduating from Bryn Mawr College, received her Ph.D in Biochemistry at Brandeis University.

Dr. Horwitz has had a continuing interest in natural products as a source of new drugs for the treatment of cancer. Her laboratory has made Taxol, a drug isolated from the yew plant, Taxus brevifolia, a major focus of its work. Although no one was interested in Taxol when she began her studies, today it is an important anti-tumor drug that has been given to over a million patients. Dr. Horwitz' research played an important role in encouraging the development of Taxol by the National Cancer Institute.

Dr. Horwitz and her collaborators demonstrated that the effects of Taxol were due to a novel interaction between the drug and microtubules, the latter being essential for the pairing and segregation of chromosomes during cell division. Her pioneering investigations and perceptive analysis of the results identified Taxol as a prototype of a new class of anti-tumor drugs. Extensive research has led to major insights into several aspects of the chemistry and biology of Taxol. Dr. Horwitz also has made significant contributions to our understanding of the molecular mechanisms underlying Taxol resistance in tumor cells.